Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][C:25]3([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: NCC1(O)CCCC1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1NCC1(O)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (54.42 g, 188.6 mmol) in chloroform (820 mL) was cooled to 0° C., and triethylamine (105 mL, 755 mmol) was added. A solution of 1-(aminomethyl)cyclopentanol (28.25 g, 245.2 mmol) in chloroform (272 mL) was added slowly over a period of 15 minutes. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The solution was washed sequentially with water (500 mL) and saturated aqueous sodium bicarbonate (750 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-{[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclopentanol.
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][N:9]1C(CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 2 h

Procedure:
To 1.20 g (2.86 mmol) of N-t-butyl-4-(1,1-dimethyl-ethoxy-carbonyl)-1 -(phenylmethylcarbonyl)piperazine-2(S)-carboxamide and 1.1 g (0.086 mmol) of 10% Pd/C was added 15 mL of methanol. The vessel was charged with hydrogen and the reaction stirred for 2 hours, filtered through Celite and washed with ethanol. The solvents were removed in vacuo to provide the title product as a foam.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([CH3:6])[CH3:5].C([Li])CCC.[CH:31]([C@@H:33]1[CH2:37][C@@H:36]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:35][N:34]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=O.C(OCC)(=O)C>O1CCCC1.CCCCCC.O>[CH3:5][CH:4]([CH3:6])[CH2:3][CH:2]=[CH:31][C@@H:33]1[CH2:37][C@@H:36]([O:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH2:35][N:34]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: O=C[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Reactant: CC(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)CC=C[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 48.5 %

Procedure:
In 11 ml of tetrahydrofuran is suspended 3.34 g of isopentyltriphenylphosphonium iodide, to which is dropwise added 4.3 ml of a 1.53 mol/L solution of n-butyllithium in n-hexane at −25° C. to −20° C. After stirring the mixture at −25° C. to −15° C. for one hour, the temperature is elevated to ambient temperature in one hour. To the reaction mixture is dropwise added 1.10 g of benzyl (2S,4R)-2-formyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate dissolved in 11 ml of tetrahydrofuran over a period of 20 minutes. The mixture thus obtained is stirred at ambient temperature for 5 hours. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to obtain 0.62 g of benzyl (2S,4R)-2-(4-methyl-1-pentenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate as a light yellow oily product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:19]([O:20][CH3:21])[CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C1CCCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCN(Cc2ccccc2)C1
Yield: 71.5 %

Procedure:
1-Benzylpiperidine-3-carboxylic acid (318 mg, 1.45 mmol) and N,O-dimethylhydroxylamine hydrochloride (287 mg, 2.94 mmol) in tetrahydrofuran (5 mL) was stirred with triethylamine (283 μL, 2.03 mmol), 1-hydroxybenzotriazole (101 mg, 0.747 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg, 2.92 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residues was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (272 mg, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([CH2:30][C:31](Cl)=[O:32])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)CC(=O)Cl
Reactant: CNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CS(C)(=O)=O)c1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide was dissolved in dichloromethane. Methylsulfonylacetyl chloride (1.2 eqs.) and triethylamine (2 eqs.) were added and the solution was stirred at room temperature. After 5 hours a further 2 eqs. of methylsulfonylacetyl chloride and 2 eqs. of triethylamine were added. The solvent was removed under vacuum and the residue was suspended in methano/0.1 M NaOH. The suspension was sonicated for 2 minutes and left stirring at room temperature for 30 minutes. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as bright yellow fluffy material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-:9].[Na+].ClOC(C)(C)C>C(#N)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: [I-]
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Oc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 40 mmol of 4-chlorophenol and 52 mmol of sodium iodide in 80 mL of acetonitrile and 16 mL of water at room temperature add 52 mmol of tert-butyl hypochlorite dropwise over a period of 30 minutes. Stir the reaction mixture for 3 hours at ambient temperature. Dilute the reaction mixture with 200 mL of ethyl acetate. Wash the resulting organic solution successively with 5% aqueous sodium thiosulfate solution and brine and dry over anhydrous magnesium sulfate. Remove the solvent and then crystallize from hexanes to yield 51% of (P9) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:9]([NH:11][OH:12])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C=O.O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([N:11]([C:9](=[O:10])[C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[NH2:1])[OH:12])=[O:23])([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)NO
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](Cc1c[nH]cn1)C(=O)N(O)C(=O)c1ccccc1C(=O)O
Reaction time: 4 h
Yield: 44.9 %

Procedure:
D-Histidine hydroxamic acid (1.9 g, 11.2 mMol) was dissolved in dimethylformamide (75 ml) and water (100 ml). Phthalic anhydride (1.65 g, 11.2 mMol) was added, the solution stirred 4 hours, evaporated to an oil which was crystallized from water/ethanol, and crystallized again from water to yield 1.6 g, m.p. 175° (dec.) of N-(2-carboxybenzoyl)-D-histidine hydroxamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:26](=[O:29])[CH2:27]Br)[O:24][CH:25]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:26]([C:27]2[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]3[C:5]([C:6]=2[NH2:7])=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)=[O:29])[O:24][CH:25]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(=O)OCc1coc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 4-chloro-2-(ethoxycabonylamino)benzonitrile (Exampe 1, step 1) and 4-acetoxymethyl-2-(bromoacetyl)furan (step 1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][NH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][S:6]([C:7]1[NH:11][CH:10]=[CH:9][N:8]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ccccc1CSc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 900 mg (4.11 mmol) of 2-(2-methylaminobenzylthio)imidazole in a mixture of 40 ml of chloroform and 10 ml of methanol was portionwise added under chilling with ice 880 mg (4.11 mmol, purity 80%) of m-chloroperbenzoic acid. The mixture was then stirred for 30 min. To the stirred mixture was added a saturated aqueous sodium hydrogencarbonate. The resulting aqueous solution was subjected to extraction with 50 ml of chloroform. The chloroform portion was taken out and the subjected to extraction with three portions of 10 ml of 0.1N aqueous NaOH and one portion of 20 ml of 0.1N aqueous NaOH to transfer a product into the aqueous fractions. The last three aqueous fractions were combined and made ammonia-alkaline by addition of 20% aqueous ammonium chloride to precipitate a crystalline product. The product was collected, washed sufficiently with water and dried under reduced pressure at room temperature to give 637 mg of the desired compound as a pale yellow crystalline product, yield 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.[Br:22]Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:20]#[N:21])=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:12]=2[Br:22])=[CH:4][CH:3]=1
Reactant: N#Cc1[nH]c(-c2ccc(Cl)cc2)cc1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(Br)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
Bromination of 2,4-bis(p-chlorophenyl)-5-cyanopyrrole is accomplished by treatment with 1 equivalent of bromine in acetic acid in the presence of anhdyrous sodium acetate yields the desired product (0.47 g, yellow solid, 44% yield, mp 98°-100° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[OH:27])#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[OH:27])[CH:3]=1)=[O:17]
Reactant: C#CC1CCCCC1O
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2CCCCC2O)c1)C(F)(F)F

Procedure:
Sonogashira coupling of bromide 25 with 2-ethynylcyclohexanol followed by flash chromatography (5-50%-EtOAc/hexanes gradient), gave 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide as a yellow oil. Yield (1.9 g, 63%): 1H NMR (400 MHz, CDCl3) δ 7.39-7.41 (m, 1H), 7.23-7.36 (m, 4H), 4.84 (q, J=4.0 Hz, 1H), 3.62-3.72 (m, 1H), 3.50-3.57 (m, 1H), 3.34-3.44 (m, 1H), 2.38-2.46 (m, 1H), 2.18 (brs, 2H), 1.90-2.10 (m, 4H), 1.66-1.84 (m, 2H), 1.40-1.53 (m, 1H), 1.16-1.40 (m, 3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:47])[C:19]([C:22]3[N:23]=[C:24]([NH:27][C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:25][CH:26]=3)=[N:20][OH:21])[C:15](=[O:48])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(Cl)Cl.[C:52](Cl)(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.[CH2:61]([NH:63][CH2:64][CH3:65])[CH3:62]>C(OCC)(=O)C.N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:47])[C:19]([C:22]3[N:23]=[C:24]([NH:27][C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[S:25][CH:26]=3)=[N:20][O:21][C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:59])[C:15](=[O:48])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:61]([NH:63][CH2:64][CH3:65])[CH3:62]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC(=O)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.683 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(hydroxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 10 ml of methylene chloride, 0.2 ml of pyridine and 0.2 ml of benzoyl chloride was stirred at room temperature for 10 minutes and was washed with water acidified to a pH of 1. The organic phase was dried, vacuum filtered and evaporated to dryness to obtain 0.737 g of raw product. The latter was dissolved in 5 ml of ethyl acetate and 0.1 ml of diethylamine was added thereto. After 10 minutes, the mixture was vacuum filtered to obtain 0.27 g of the syn isomer of diethylamine 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(phenylcarbonyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:28][CH2:27]1)#[N:19]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-cyanophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 50° C. to yield 4-[4-(2-cyano-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M]+=408.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[N:8][N:7]=[C:6]2Cl)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:6]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]=1
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Reactant: COc1ccc(CN)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Yield: 55.6 %

Procedure:
66.2 g of 6-cyano-1,4-dichlorophthalazine and 92 g of 3-chloro-4-methoxybenzylamine were suspended in 1,200 ml of tetrahydrofuran. After adding 250 ml of triethylamine, the resulting mixture was heated under reflux for 6 hours. The resulting crystals were filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography (toluene:tetrahydrofuran=10:1) to give 59 g of 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine as pale yellow crystals. M.p.: 213.0-214.5° C., Mass 359(MH+),
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([S:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=2[N:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrCc1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(SCc3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[NH:17])[NH2:16].[C:24](O[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>O1CCCC1.O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[C:6]([N:9]1[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:10]1)(=[NH:7])[NH2:8].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:20][CH2:19]1)(=[NH:16])[NH2:17]
Reactant: N=C(N)N1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.4 %

Procedure:
2.50 g of 1-amidinopiperazine hemisulfate were dissolved in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and a solution of 3.40 g of di-t-butyl dicarbonate in 10 ml of tetrahydrofuran was added to the resulting solution, after which the mixture was stirred at room temperature for 2.5 hours. At the end of this time, the tetrahydrofuran was removed from the reaction mixture by distillation under reduced pressure, the insolubles were filtered off and the filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted with ethanol (twice, each time with 50 ml) and methanol (twice, each time with 50 ml). The extract was evaporated to dryness to obtain 2.48 g of the title compound, as crystals, melting at 278° C. (with decomposition).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][O:11][CH2:10][CH2:9][O:8]1)(=O)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:31])[C:22]([C:26]([O:28]CC)=[O:27])=[CH:23][NH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+].Cl>CN(C=O)C.O>[O:8]1[CH2:9][CH2:10][O:11][CH2:12][C@@H:7]1[CH2:6][N:24]1[CH:25]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:21](=[O:31])[C:22]([C:26]([OH:28])=[O:27])=[CH:23]1
Reactant: CS(=O)(=O)OC[C@H]1COCCO1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cn(C[C@H]2COCCO2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
(2R)-1,4-Dioxan-2-ylmethyl methanesulfonate (95 mg) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg) and cesium carbonate (264 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. (2R)-1,4-Dioxan-2-ylmethyl methanesulfonate (32 mg) was added at room temperature. The reaction mixture was stirred at 80° C. overnight. (2R)-1,4-Dioxan-2-ylmethyl methanesulfonate (32 mg) was added at room temperature. The reaction mixture was stirred at 100° C. for three hours and then returned to room temperature. A 1 N aqueous sodium hydroxide solution (2 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for one hour. A 1 N aqueous hydrochloric acid solution and water were added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and then dried to give 101 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.I[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][NH:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:30]=[CH:31][C:32]([C:50]3[N:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: IN1C=CC=CN1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cccnn5)cc4)nc32)c1
Temperature: 100 °C
Yield: 33.6 %

Procedure:
A solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (prepared as described in example 35, 0.50 g, 0.81 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-iodopyridazine (0.25 g, 1.2 mmol), cesium carbonate (0.527 g, 1.61 mmol), Pd(dppf)2Cl2 (0.06 g, 0.08 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyridazin-3-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide (0.155 g, 34% yield). 1H NMR (DMSO-dg, 400 MHz) δ 10.15 (br, 1H), 9.22 (m, 1H), 8.52 (s, 1H), 8.22 (d, 1H), 8.06 (m, 3H), 7.83 (m, 1H), 7.81 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.42-7.48 (m, 4H), 7.20 (m, 1H), 3.02 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 569.9.