Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH2:18][CH3:19])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(CC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.4 g, 6.8 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.28 g, 2.04 mmol) was added and stirred for further at 100 deg C. for 18 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.025 g, 10% yield). 8-Chloro-5-[2-(6-ethyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.07 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.07 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 32% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:31]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20].[BrH:33].O.C([O-])(O)=O.[Na+].[C:40]([OH:43])(=O)[CH3:41]>>[C:40]([O:1][CH:2]([CH2:31][Br:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20])(=[O:43])[CH3:41]
Reactant: Br
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCCCCCCC(O)CO)c(=O)n2C
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.5 h

Procedure:
1-(16,17-Dihydroxyheptadecyl)-3,7-dimethylxanthine (1.10 g, 2.44 mmol) was stirred with HBr (3.50 mL of a 30% solution in acetic acid, 17.1 mmol) for 4 hours. The mixture was then added over 10 minutes to water (50 mL), and NaHCO3 (10 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (3×30 mL), the combined organic phases were dried using magnesium sulfate and the solvent was evaporated to obtain a residue of 1-(16-acetoxy-17-bromoheptadecyl)-3,7-dimethylxanthine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.C(N(CC)C(C)C)(C)C.[C:20]([O:24][C:25]([O:27]C(OC(C)(C)C)=O)=O)([CH3:23])([CH3:22])[CH3:21].[I-:35].[Na+]>C1COCC1>[C:20]([O:24][C:25]([NH:1][C@@H:2]([CH2:7][CH2:8][I:35])[C:3]([O:5][CH3:6])=[O:4])=[O:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)CCBr
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To an ice cold suspension of (S)-methyl 2-amino-4-bromobutanoate, 1.00 HCl (see WO2003/101948 A2, 4.42 g, 19.02 mmol) and N,N-diisopropylethylamine (9.97 mL, 57.1 mmol) in anhydrous THF (50 mL) is slowly added a solution of di-tert-butyldicarbonate (4.36 g, 19.97 mmol) in anhydrous THF (8 mL). The reaction is stirred for 18 h while warming to room temp. The solvent is removed in vacuo, and the residue is partitioned between EtOAc (450 mL) and aqueous saturated ammonium chloride (30 ml). The organic layer is washed with aqueous saturated sodium bicarbonate (1×30 mL), water (1×30 mL), brine (1×30 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue is dissolved in acetone (450 mL). treated with sodium iodide (14.25 g, 95.1 mmol) and the reaction is refluxed for 18 h. The reaction is cooled to room temp, filtered thru a ground glass frit and the solvent removed in vacuo. The residue is dissolved in EtOAc (450 mL), washed with water (3×40 mL), brine (1×40 mL), dried over Na2SO4, filtered, evaporated to dryness and purified by BIOTAGE® Silica gel chromatography on a 80 g Thompson Single Step silica cartridge using 100% CH2Cl2 over 10 column volumes to give 3.9 g (60%) of the title compound as a thick oil. LC/MS (Condition A): ret. T=3.40 min, (M+Na) 366.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:47])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH2:38][O:39]C3CCCCO3)[N:35]=[C:34]([CH3:46])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:49](O)([C:51]([F:54])([F:53])[F:52])=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:49]([C:51]([F:54])([F:53])[F:52])=[CH:10][C:9]2[NH:21][C:22](=[O:47])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:46])[N:35]=[C:36]([CH2:38][OH:39])[CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M301) (0.54 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (240 mg, 64%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20](O)[CH2:21][CH:22]=[CH2:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.CCOC(C)=O>[N:34]([CH:20]([C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)[CH2:21][CH:22]=[CH2:23])=[N+:35]=[N-:36]
Reactant: C=CCC(O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCC(N=[N+]=[N-])c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-ol (0.14 g, 0.41 mmol) in DCM (10 mL) was added thionyl chloride (0.045 mL, 0.61 mmol). The reaction mixture was stirred for about 8 h at ambient temperature and then EtOAc and saturated aqueous NaHCO3 (10 mL each) were added. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concd in vacuo. The crude chloride was dissolved in DMF (10 mL) and sodium azide (0.159 g, 2.45 mmol) was added to the reaction mixture. The reaction mixture was stirred for about 15 h at ambient temperature and then EtOAc and saturated aqueous NaHCO3 (10 mL each) were added to the reaction mixture. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel eluting with 10-60% EtOAc in heptane to provide 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.153 g, 87%) as an oil: LC/MS (Table 1, Method a) Rt=2.84 min; MS m/z: 369 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].S(=O)(=O)(O)O.[OH:10][CH2:11][C:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])O)[OH:17])[OH:15])=[O:13].[OH-].[Na+].CO[C:26](C)([CH3:28])[CH3:27]>CCCCCC.C(O)(C)C>[CH3:1][C:2]1([CH3:4])[O:17][C@@H:16]2[C@@H:18]([CH2:20][O:21][C@@:12]3([CH2:11][OH:10])[O:13][C:26]([CH3:28])([CH3:27])[O:15][C@H:14]32)[O:3]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COC(C)(C)C
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(CO)OC(C)(C)O[C@@H]23)O1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Under nitrogen, acetone (144.0 L, 113.0 kg, 1946 mol) was cooled to 0°-10° C. With stirring, concentrated sulfuric acid (7.2 L, 13.2 kg, 135.6 mol) was added gradually (approx. 0.5 h) so that the temperature did not exceed 20° C. (jacket temperature at -15° C.). External cooling was discontinued and D-fructose (12.0 kg, 66.6 mol) was added gradually (in 2.0 kg portions) over 2 h while maintaining the temperature between 8°-15° C. The suspension was stirred at room temperature for an additional 2-3 h after all the fructose had dissolved. The solution was then cooled to 5° C. and 50% sodium hydroxide (24.0 kg, 297.6 mol) was added at a rate so as to maintain the solution temperature below 20° C. (addition was complete in 1 h with a jacket temperature at -15° C.). The resulting slurry was centrifuged to remove the precipitated salt (sodium sulfate). Solvent was removed from the filtrate by vacuum distillation and the residual oil was stored at room temperature. The semi-solid reaction product was dissolved in t-butyl methyl ether (48.8 kg, 66.4 L). The solution was washed with distilled water (2×9.0 L) and concentrated to give an oil. The oil was dissolved in hexane (24.0 L)/isopropanol (3.5 L) with gradual warming to 60° C. The product crystallized with cooling. The solid was collected by centrifugation and dried in a vacuum oven at 38° C. for 8.0 h to give 10.8 kg (62.4% yield, 100.8% purity by GLC) of a white solid, mp 95°-96° C.
Reaction SMILES: C(O[C:9]([N:11](C)[C@@H:12]([C:20]([N:22]1[CH2:49][CH2:48][CH2:47][C@H:23]1[C:24]([NH:26][C@H:27]([CH:45]=[O:46])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:44])[NH:33]C(OCC1C=CC=CC=1)=O)=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.O.[S:52](=[O:56])(=[O:55])([OH:54])[OH:53].C(OCC)(=O)C.N1C=CC=CC=1CC(O)=O.O>C(O)C.[Pd]>[S:52]([OH:56])([OH:55])(=[O:54])=[O:53].[CH3:9][NH:11][C@@H:12]([C:20]([N:22]1[CH2:49][CH2:48][CH2:47][C@H:23]1[C:24]([NH:26][C@H:27]([CH:45]=[O:46])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:44])=[O:25])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)Cc1ccccn1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N

Procedure:
23.1 g (0.03 mole) of N-benzyloxycarbonyl-N-methyl-D-phenylalanyl-L-prolyl-Nω -benzyloxycarbonyl-L-arginine-aldehyde (Example 1, Step 2) are dissolved in 150 ml of ethanol, 50 ml of deionized water and 48 ml of N sulfuric acid are added and the mixture is submitted to hydrogenolysis in the presence of 3 g of a 10 percent Pd/C catalyst. The progress of the hydrogenolysis is monitored by thin-layer chromatography in a developing solvent of ethyl acetate-pyridine-acetic acid-water-30:20:6:11 (Rf values of the starting material, intermediary and final product about 0.9, 0.7 and 0.4, respectively). After completed reaction the catalyst is filtered and washed three times with 30 ml of deionized water. The filtrate and washings are combined and concentrated to about 100 ml in a rotary evaporator. The aqueous residue is diluted to about 200 ml with deionized water and its pH is controlled. If it is not between 6.0 and 6.5, it is adjusted with 0.1N sulfuric acid or an ion-exchange resin in OH cycle (i.e. AG 1X8), then the solution is freeze-dried. Yield 12.4 g (75%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:24]=[CH:25][C:18]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:3][C@@H:4]([CH2:9][O:10][C@H:11]([CH3:15])[CH2:12][O:13][CH3:14])[C:5]([O:7][CH3:8])=[O:6])=[C:18]2[CH:25]=[N:24]1
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Sodium hydride (94 mg, 2.34 mmol) was added to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (300 mg, 1.56 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (538 mg, 2.03 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was neutralized with 1M citric acid, diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (358 mg, 54.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][N:3]=1.[CH:10](=O)[CH:11]([CH3:13])[CH3:12].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C=O
Reactant: NNc1cnc(Cl)cn1
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nnc2cnc(Cl)cn12
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
The 2-chloro-5-hydrazinylpyrazine (0.325 g, 2.248 mmol) was suspended in DCM (4 mL) then the isobutyraldehyde (0.195 g, 2.70 mmol) was added. The mixture was stirred for about 30 min, the solvent was concentrated under reduced pressure and the solid was dissolved in DCM (4 mL). Iodobenzene diacetate (0.724 g, 2.24 mmol) was added and the solution was stirred at ambient temperature for about 2 h. The mixture was diluted with DCM (20 mL), extracted with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as an eluent to give the title compound (0.278 g, 63%): LC/MS (Table 1, Method g) Rt=1.74 min; MS m/z: 197.1 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([CH2:16][C:17]#[N:18])[CH2:3]1.N.[H][H]>[Ni].CO>[NH2:18][CH2:17][CH2:16][N:4]1[CH2:5][CH2:6][C@@H:7]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:2]([OH:1])[CH2:3]1
Reactant: [H][H]
Reactant: N#CCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Yield: 91.6 %

Procedure:
A mixture of 12 parts of trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidineacetonitrile and 320 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 11.2 parts (91.6%) of trans-1-(2-aminoethyl)-4-[(phenylmethyl)amino]-3-piperidinol as a residue (interm. 17).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:28]=2[N:29]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH:34][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([O:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:15]=3)=[CH:30][C:28]=2[N:29]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4cccc(Oc5ccccc5)c4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of 3-phenoxy-benzoic acid (0.247 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 3-phenoxy-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.200 g, 0.768 mmol) and pyridine (0.06 mL) in CH2Cl2 (5.0 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (3×25 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (5×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.163 g, 46%). mass spectrum (m/e): 457.0 (M+1), 455.0 (M−1). 1H NMR (400 MHz, CD3OD): δ 7.72-7.67 (m, 2H), 7.60-7.57 (m, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 2H), 7.35-7.28 (m, 2H), 7.22-7.15 (m, 2H), 7.09-7.05 (m, 2H), 4.18-4.09 (m, 1H), 3.12 (s, 3H), 3.06-3.00 (m, 2H), 2.35 (s, 3H), 2.24 (dt, J=12.4, 2.4 Hz, 2H), 2.03-1.92 (m, 2H), 1.87-1.80 (m, 2H).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](Br)=[O:4].[CH:7]1[CH2:12]CC=[CH:9][CH:8]=1.[CH2:13](N(CC)CC)C>CCCCCC>[CH3:12][CH:7]=[CH:8][CH2:9][CH2:6][CH2:2][C:3](=[O:4])[CH3:13]
Reactant: CC(Br)C(=O)Br
Reactant: CCN(CC)CC
Reactant: C1=CCCC=C1
Solvent: CCCCCC
Product: CC=CCCCC(C)=O

Procedure:
81.3 g (0.38 mol) of 2-bromopropionyl bromide in 100 ml of hexane were added over a period of 1 hour to 39.8 g (0.5 mol) of 1,3-cyclohexadiene and 38.6 g (0.38 mol) of triethylamine while maintaining the temperature below 40° C. by occasional cooling. After an additional 3 hours at room temperature the precipitated triethylamine hydrobromide was removed by filtration. The filtrate was evaporated and the residue was purified by distillation under reduced pressure and subsequently by chromatography on silica gel using 4% diethyl ether in hexane for the elution. There were obtained 9.48 g of exo-8-bromo-8-methylbicyclo[4:2:0]oct-2-en-7-one and 5 89 g of endo-8-bromo-8-methylbicyclo[4:2:0]oct-2-en-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=O)[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20](=[O:31])[NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].Cl.CN.C[CH2:36][N:37]=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16](=[O:18])[NH:37][CH3:36])[C:11](=[O:19])[CH:10]=[N:9]2)=[CH:4][C:3]=1[C:20]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)NCCc3ccccc3Cl)c2)c1=O
Reaction time: 5 h
Yield: 27.3 %

Procedure:
A slurry of (2-{4-Chloro-3-[2-(2-Chloro-phenyl)-ethylcarbamoyl]-phenyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-acetic acid (71.4 mg, 0.154 mmol), methylamine HCl (15.6 mg, 0.231 mmol), EDCI (44.4 mg, 0.231 mmol), and DMAP (75.5 mg, 0.616 mmol) in DMF (1.0 mL) were stirred at ambient temperature for 20 hours. The reaction was diluted with 1N HCl, and let stir for 5 hours. The crude was filtered and triterated from hexane to give the title compound (20 mg). LCMS (m/z) 476.1 M+1.
Reaction SMILES: P([O:13][CH2:14][C@H:15]1[O:19][C@@H:18](N2C3N=CN=C(N)C=3N=C2)[C@H:17](O)[C@@H:16]1[OH:31])(OP(OP(O)(O)=O)(O)=O)(=O)O.[CH3:32][C:33]1[C:43](=O)[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:35](=[O:36])[C:34]=1[CH2:45]/[CH:46]=[C:47](/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\[CH3:48].[OH-:65].[Na+]>[Cl-].[Na+]>[CH:32]1[CH:40]=[CH:41][C:42]([CH:37]2[C:35](=[O:36])[C:34]3[CH:45]=[CH:46][CH:47]=[CH:48][C:39]=3[C:38]2=[O:65])=[CH:43][CH:33]=1.[CH3:46][C:45]([CH2:34][CH:35]([C:15]1[C:14](=[O:13])[O:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:17]=2[C:16]=1[OH:31])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:65]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: CC1=C(C/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Product: O=C1c2ccccc2C(=O)C1c1ccccc1

Procedure:
Control, blank, and experimental reaction mixtures were made for each experiment. Control and blank reaction mixtures were made up with vitamin K and without vitamin K, respectively. Experimental reaction mixtures contained both vitamin K and a vitamin K antagonist. The control reaction mixture contained 3.00 ml of microsomal suspension, 0.81 ml of buffer II, 1.20 ml of an ATP-generating system (final concentrations: 1 mM ATP, 10 mM phosphocreatine, 2.5 mM Mg[acetate]2 ·4H2O, 20 μg/ml creatine phosphokinase [52 U/ml]), 0.60 ml of NADH (final concentration 2 mM), 0.30 ml of dithiothreitol (final concentration 7 mM) dissolved in buffer II, 0.060 ml of NaH14CO3 (1.0 μCi/μl; added 0.5 min prior to reaction initiation), and at the time of reaction initiation 0.030 ml of vitamin K1 (final concentration 20 μg/ml) diluted in 0.85% sodium chloride solution. This vitamin K concentration is associated with maximal in vitro incorporation of added H14CO3 into vitamin K-dependent substrate proteins (J. Biol. Chem. 251, 2770-2776). The blank reaction mixture consisted of the same components except that vitamin K was replaced by an equal volume of isotonic saline. The experimental reaction mixtures were made up in the same way as the control reaction mixtures with the exceptions that: (1) a volume of buffer II was replaced by a volume of buffer II containing an inhibitor of vitamin K-dependent carboxylation, and (2) all individual volumes were two-thirds of those in the control reaction mixtures. The sodium salts of TCP, phenindione, and warfarin were formed in aqueous sodium hydroxide solution (J. Am. Chem. Soc. 83, 2676-2679) and were freely soluble in buffer II at all concentrations used in these studies. Chloro-K1 was formulated as an oil-in-water emulsion with Tween 80 (5% v/v final concentration), while chloro-K3 was formulated as a suspension in Tween 80 (5% v/v final concentration) (Molecular Pharmacology 10, 373-380).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([N+:10]([O-])=O)[C:4]=1[CH3:13]>C1COCC1.[H][H].[Ni]>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:14])[CH3:1])=[C:4]([CH3:13])[C:5]=1[NH2:10]
Reactant: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1c(N(C)C)ccc(Br)c1N
Yield: 90.5 %

Procedure:
15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is dissolved in about 200 ml of THF and hydrogenated at 20° C. under 5 bars pressure of hydrogen using Raney nickel as catalyst. 12 g of 2-bromo-5-dimethylamino-6-methylaniline is obtained as a brown oil.