Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19](CO)[OH:20])[OH:18])[OH:16])[OH:14].C(=O)([O-])[O-].[Ca+2].C(O)C>P([O-])([O-])([O-])=O>[OH:6][CH2:5][C:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])=[O:7].[CH2:12]([OH:11])[C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(CO)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 24 h

Procedure:
D-arabitol and D-glucose were dissolved in 0.1M phosphate buffer solution(pH 6.0) to final concentrations of 5% (w/v) and 1% (w/v), respectively, and 5 ml each of the solution was dispensed in a test tube. The bacterial cells in a wet weight of about 10% (w/v) and 2% (w/v) of calcium carbonate were added to this reaction mixture, and a reaction with shaking was run at 30° C. In the lot where a carbon source was added, 1% (w/v) glucose was added at the initiation of the reaction and 5% (v/v) ethanol was added after 6 hours from the initiation of the reaction for further reaction. The reaction was stopped after 24 hours from the initiation thereof. After the bacterial cells were removed by centrifugation, the reaction product was analyzed by HPLC. In the case where no carbon source was added, a portion of D-xylulose remained unreacted and the amount of xylitol produced was 0.98% (w/v) (yield of 20% based on D-arabitol) whereas in the case where a carbon source was added, the efficiency of conversion reaction was increased and xylitol was produced and accumulated in a yield as high as 2.57% (w/v) (yield of 51% based on D-arabitol).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC[CH2:11][CH2:12][C:13]#[N:14].[C:15](=O)(O)[O-].[Na+]>>[C:13]([CH2:12][CH2:11][CH2:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[N:14]
Reactant: N#CCCCCl
Reactant: O=C([O-])O
Reactant: CNc1ccccc1
Agent: [Na+]
Product: CN(CCCC#N)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To N-methylaniline (25 g) was added 4-chlorobutyronitrile (25 ml) and the mixture was stirred at 110° C. for 24 hours. After cooling, the mixture was neutralized with an aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to distillation under reduced pressure to obtain the desired compound (21.5 g) as pale yellow oil.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:41][C:40]=2[O:51][CH3:52])[C:35]([Cl:53])=[CH:34][N:33]=1.C(=O)([O-])[O-]>C(O)(C)C.C(Cl)Cl>[Cl:53][C:35]1[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][C:40]=2[O:51][CH3:52])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(F)cc21
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (70.5 mg, 0.303 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (58 mg, 0.28 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (98 mg, 0.28 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min). MP-Carbonate (2.69 mmol/g loading; 0.21 g, 0.57 mmol) and DCM (2 mL) were added and the mixture stirred for 1 h, then filtered onto a 5 g SiO2 cartridge, which which was air dried. The sample was chromatographed (ISCO, 2×12 g SiO2, 0-50% EtOAc:Hex) to afford 5-Chloro-N*2*-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as a lavender film (43 mg, 29%). LCMS 529 (M+H), 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.7 Hz), 8.00 (s, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 6.75 (s, 1H), 6.60 (d, 1H, J=13.2 Hz), 6.55 (m, 2H), 4.08 (t, 2H, J=5.6 Hz), 3.91 (s, 3H), 3.88 (t, 4H, J=4.6 Hz), 3.17 (m, 8H), 1.98 (m, 2H), 1.21 (t, 3H, J=7.0 Hz); 19F-NMR: −135.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:25])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:25][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (0.66 g, 3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (0.59 g, 3.13 mmol) and N,N-diisopropylethylamine (0.81 g, 6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.11 mg, 9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:26]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCBr
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Product: CCCCCCCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 65.7 %

Procedure:
In a similar manner to Example 10b), by reaction of 2 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) benzaldehyde [prepared in Example 16(a)] with 1.1 ml (6.8 mmol) of 1-bromoheptane, 1.88 g (72%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1.[CH3:22][NH2:23].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH3:22])[C:12]=2[CH2:19][CH2:20][CH3:21])[CH:3]=1
Reactant: CCCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CCCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-propylphenoxy)-benzonitrile (0.35 g, 1.1 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 9.0 mL, 72 mmol), and the reaction mixture stirred 18 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (127 mg, 1.1 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(3-methylaminomethyl-2-propyl-phenoxy)-benzonitrile fumarate (354 mg, 75%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxan and treated with 0.047 g (0.00055 mol) of piperazine and 0.7 ml of triethylamine. The mixture was stirred at room temperature for 20 hrs. and subsequently at 40° C. for 3 hrs., the solvent was then removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.14 g (62%) of 1-[6-bromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridin-2-yl]-piperazine as yellow crystals; m.p.: 160-162° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22](O)=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(CC)CC.O.[CH3:31][CH2:32][CH2:33][CH2:34]CC>>[C:1]1([NH:7][C:8]2([C:22](=[O:23])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CCCCC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (-5° C.) suspension of 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid in 525 parts of dry 1,1'-oxybisethane, are added dropwise 228.5 parts of 1-lithiumbutane solution 20% in hexane at 0° C. Upon completion, stirring is continued for 3 hours at 0° C. The reaction mixture is decomposed by addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 2.5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2,2'-oxybispropane and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleum-ether, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]-1-pentanone; mp. 71.3° C.
Reaction SMILES: C(O)=[O:2].OO.[S:6]([O-:9])([O-:8])=[O:7].[Na+].[Na+].[OH-].[Na+].[CH:14]([O:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(OCC)(=O)C>[OH:2][CH:15]1[CH:20]2[CH:18]3[CH:19]([CH2:16][CH:14]1[O:17]3)[S:6](=[O:9])(=[O:8])[O:7]2
Reactant: O=CO
Reactant: CC(C)OC(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=S1(=O)OC2C(O)C3CC1C2O3
Temperature: 10 °C
Reaction time: 40 h

Procedure:
Into a three-necked flask having an inner volume of 500 mL equipped with a stirrer, a thermometer and a dropping funnel, the whole amount of “Concentrated Liquid F” obtained above was charged, and cooled down to 10° C. 99% Formic acid (30.0 g, 0.645 mol) was weighed into a dropping funnel, and added dropwise to the reaction system so that the inner temperature of the reaction system was maintained in a range of 15 to 18° C. After that, the inner temperature was raised up to 34 to 35° C. by heating, and then 30% hydrogen peroxide aqueous solution (45.2 g, 0.399 mol) weighed and contained in another dropping funnel was added dropwise to the reaction system over 3 hours. After completion of the dropping, the inner temperature of the reaction system was also maintained at around 35° C. After 40 hours from completion of the dropping, the reaction liquid was analyzed by HPLC to confirm that conversion ratio of sodium 7-oxa-5-bornene-2-sulfonate was 98.1%. After cooling down the reaction liquid to 20° C., sodium sulfite was added slowly to the reaction system so that the inner temperature of the reaction system was maintained in a range of 20 to 25° C. until a starch paper did not detect hydrogen peroxide. Subsequently, 30% sodium hydroxide aqueous solution was added slowly to adjust pH of the reaction liquid at 6.8 so that the inner temperature of the reaction system was maintained in a range of 20 to 25° C. The reaction liquid was extracted with ethyl acetate (100 g) three times, and the resultant organic layers were combined, washed with water (50 g), and then concentrated under the reduced pressure until forming of white solid could be seen. Ethyl acetate (20 g) was added, and then isopropyl ether (40 g) as also added in a heated state at 60° C., then the mixture was cooled down to 1° C. at a rate of about 15° C./hour, to precipitate crystal of the product. After filtering the precipitated crystal, the filtered out crystal was washed with isopropyl ether (40 g) at 1° C., and dried at 30° C. for 2 hours under the reduced pressure, to obtain 2-hydroxy-4,8-dioxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide (6.84 g, purity: 98.9%, 0.035 mol). It should be noted that, yield of the product from 7-oxa-5-norbornene-2-sulfonyl chloride was 14.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28].O>CN(C)C=O.[Cu]I.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>[CH3:30][Si:29]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate (10 g, 30.4 mmol), copper (I) iodide (579 mg, 3.04 mmol), dichlorobis(triphenylphosphine)palladium (II) (2.13 g, 3.03 mmol) and triethylamine (8.5 ml, 61.0 mmol) in anhydrous N,N-dimethylformamide (50 ml) was added ethynyltrimethylsilane (6.3 ml, 45.5 mmol). After stirring overnight at 50° C., water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70→35:65) to give tert-butyl 2-({4-[(trimethylsilyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (7.1 g, yield 68%) as a greeny brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:31][C:32]([NH2:34])=[O:33]>CN(C)C=O.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][N:19]([CH2:31][C:32]([NH2:34])=[O:33])[C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: NC(=O)CCl
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2c(cn1CC(N)=O)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 4.0 g (11.7 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo-[3,4-d][2]benzazepine were added to an ice-cooled solution of 1.6 g (14.2 mmol) of potassium t-butoxide in 60 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 1.4 g (15.0 mmol) of 2-chloroacetamide were added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a red residue. Purification of the residue by column chromatography (silica gel, 100 g; eluent, 50% ether in tetrahydrofuran) gave 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as a yellow solid. Recrystallization from ethyl acetate gave colorless needles, mp 142°-145° C.
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][N:8]=1
Reactant: BrBr
Reactant: N[C@H](CNc1nccc(-c2ccncc2)n1)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N[C@H](CNc1ncc(Br)c(-c2ccncc2)n1)Cc1ccccc1
Reaction time: 48 h

Procedure:
Bromine (787 μl, 15.28 mmol) was added to a stirring solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-4-(4-pyridyl)-pyrimidine (2.33 g, 7.64 mmol) in chloroform (25 ml). Stirring was continued for 2 d. The mixture was partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with brine, dried and evaporated. The resultant product was purified on a column of silica gel (dichloromethane-methanol-conc. ammonium hydroxide=92:8:0.6). MS (m/z): 384.0, 386.0 (M+H)+; C18H18BrN5 requir. 384.3.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13](=[C:14]=[O:15])[N:12]([CH2:16][CH3:17])[C:11]2[N:10]=[C:9]3[CH:18]=[C:19](F)[C:20]([F:22])=[CH:21][C:8]3=[CH:7][C:6]=2[C:5]1=[O:24])[CH3:2].Cl.Cl.[CH3:27][N:28]([CH3:33])[CH:29]1[CH2:32][NH:31][CH2:30]1.[OH2:34]>>[CH3:27][N:28]([CH3:33])[CH:29]1[CH2:32][N:31]([C:19]2[C:20]([F:22])=[CH:21][C:8]3[C:9]([CH:18]=2)=[N:10][C:11]2[N:12]([CH2:16][CH3:17])[C:13](=[C:14]=[O:15])[CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:24])[C:6]=2[CH:7]=3)[CH2:30]1.[CH3:27][N:28]([CH3:33])[CH:29]1[CH2:32][N:31]([C:19]2[C:20]([F:22])=[CH:21][C:8]3[C:9]([CH:18]=2)=[N:10][C:11]2[N:12]([CH2:16][CH3:17])[CH:13]=[C:4]([C:4]([O:3][CH2:1][CH3:2])=[O:34])[C:5](=[O:24])[C:6]=2[CH:7]=3)[CH2:30]1
Reactant: CCOC1C(=O)c2cc3cc(F)c(F)cc3nc2N(CC)C1=C=O
Reactant: O
Reactant: CN(C)C1CNC1
Agent: Cl
Product: CCOC(=O)c1cn(CC)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Product: CCOC1C(=O)c2cc3cc(F)c(N4CC(N(C)C)C4)cc3nc2N(CC)C1=C=O
Temperature: 20 °C

Procedure:
8-(3-Dimethylamino-1-azetidinyl)-3-ethoxy-carbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 1.7 g of 3-ethoxy-carbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, and 1.3 g of 3-(dimethyl- amino)azetidine dihydrochloride. After reaction, the reaction mixture, cooled to approximately 20° C., is poured into 50 cm3 of water and extracted with 3 times 100 cm3 of dichloromethane. The combined organic extracts are washed with 3 times 150 cm3 of water and dried over magnesium sulphate. After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C. the residue is taken up with 50 cm3 of ethyl ether, filtered off and washed with twice 50 cm3 of the same solvent. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 232° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: CC(=O)NC(C)c1ccc(CCl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Product: CC(=O)NC(C)c1ccc(CN2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl)piperazine instead of phenylpiperazine and N-(1-(4-chloromethylphenyl)ethyl)acetamide obtained in Example 66(3) instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound was obtained as white crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([NH:22][CH3:23])[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:34][C:35](=[O:37])[CH3:36].[OH-].[Na+]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([N:22]([CH3:23])[CH2:34][C:35](=[O:37])[CH3:36])[N:5]=1)[CH3:2]
Reactant: CCSc1nc(NC)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCSc1nc(N(C)CC(C)=O)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 140 °C
Yield: 31.1 %

Procedure:
To a solution of 150 mg (0.45 mmol) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-(methyl-amino)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 123) in NMP (1 ml) were added 229 μl (1.35 mmol) DIPEA and 39 μl (0.50 mmol) chloroacetone. The mixture was heated in the MW to 140° C. for 40 min and subsequently partiotionated between a 1M aq. NaOH sol and EtOAc. The organic layer was separated, washed with a 1M aq. NaOH sol, water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 13:7) provided 53 mg (0.14 mmol, 30%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(2-oxo-propyl)-amino]-pyridine-3-carboxylic acid amide (example 253). [M+H]+ 390.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1
Product: COc1cccc(-c2nnc(Cl)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(3-methoxyphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2([CH3:31])[CH2:26][CH2:25][C:24]3[C:19](=[C:20]([CH3:30])[C:21]([CH3:29])=[C:22]([CH3:28])[C:23]=3[CH3:27])[O:18]2)=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:32][C:33](N)=[S:34].S1(CCCC1)(=O)=[O:37].Cl>COCCO>[CH3:31][C:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:2]3[S:34][C:33](=[O:37])[NH:32][C:3]3=[O:4])=[CH:14][CH:13]=2)[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([CH3:30])[C:21]([CH3:29])=[C:22]([CH3:28])[C:23]=2[CH3:27])[O:18]1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(C)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Product: Cc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
Following a procedure similar to that described in Example 1, but using 361 mg of ethyl 2-chloro-3-[4-(2,5,6,7,8-pentamethylchroman-2-ylmethoxy)phenyl]propionate (prepared as described in Preparation 33), 309 mg of thiourea, 3 ml of sulfolane, 10 ml of ethylene glycol monomethyl ether and 5 ml of 3N aqueous hydrochloric acid, 290 mg of the title compound were obtained as a white powder, softening at 62°-64° C.