Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([C:40](Cl)=[O:41])[CH:37]=[N:38][CH:39]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[O:41])[CH:37]=[N:38][CH:39]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (300 mg) and triethylamine (0.33 ml) in 1,4-dioxane (10 ml) was added 5-bromo-3-pyridylcarbonyl chloride·hydrochloride (304 mg). The mixture was stirred at room temperature for 15 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-[3-[(5-bromo-3-pyridyl)carbonylamino]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (256 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1)[CH3:8].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O.O.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>[CH2:7]([O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13][CH:12]=1)[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
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+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1
Yield: 57 %

Procedure:
Na2CO3 (228 mg, 2.16 mmol) was added to a stirred solution of 6-chloro nicotinic acid ethyl ester (200 mg, 1.08 mmol) in toluene:H2O (5:1, 6 mL). Pd (PPh3)4 (250 mg, 0.216 mmol) and phenylboronic acid (168 mg, 1.29 mmol) were then added and the reaction mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 140 mg (64.4% yield) of 6-phenyl-nicotinic acid ethyl ester. LCMS Purity %: 98.2
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])#[N:2].N1C=CC=CC=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[C:1]([CH2:3][C:4]([O:7][C:14]([Cl:16])=[O:15])([CH3:6])[CH3:5])#[N:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(O)CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CC#N)OC(=O)Cl
Temperature: 25 °C

Procedure:
Chloroformic cyanotert. butyl ester is prepared by reacting cyanotert butanol (10 g, 100 mMole) and pyridine (10 g, 125 mmole) in dichloromethane (150 ml) at about -40° C. together with liquid phosgene (-70° C., 40 ml, 600 mMole). The mixture is allowed to warm to room temperature and stirred over night. It is then extracted with ice cold aqueous hydrochloric acid (1N) washed twice with ice water immediately dried by shaking several times with fresh anhydrous sodium sulfate, the aqueous phases and the sodium sulfate are twice reextracted with a small amount of dichloromethane, and the combined organic phases are evaporated under reduced pressure (20° C. bath) to yield the product (17 g, 100% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[CH:4]=[N:3]1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C(#N)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:18](=[O:19])[NH:10][C:5]=2[CH:4]=[N:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1ncc([N+](=O)[O-])c1C(N)=O
Solvent: CC#N
Product: Cn1ncc2[nH]c(=O)[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
This compound was prepared following the method described in WO2008/071650. To a stirred solution of 1-methyl-4-nitro-1H-pyrazole-5-carboxamide (1.27 g, 9.06 mmol) in acetonitrile (35.6 mL) refluxed at 100° C. was added N,N-carbonyldimidazole (1.91 g, 11.78 mmol, 1.3 eq.) proportion wise over 1 hour. The reaction mixture was stirred at 100° C. under N2 for 18 hours. The resultant precipitate was filtered, rinsed well with cold acetonitrile, and pumped dry on high-vac to yield 1.38 g (91.5%) of a white solid. 1H NMR (DMSO-d6, 500 MHz) δ ppm 11.04 (broad d, 2H), 7.34 (s, 1H), 4.04 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C@@H:4]([C@H:13]([CH3:16])[O:14][CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Li+].[OH-]>O1CCOCC1.O>[C:6]([NH:5][C@@H:4]([C:3]([OH:17])=[O:2])[C@H:13]([CH3:16])[O:14][CH3:15])([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
To a solution of N-Boc-O-methyl-D-threonine methyl ester (8.09 mmol) in 1,4-dioxane (10 mL) is added a solution of LiOH (24.3 mmol) in water (20 mL). After stirring for 2-3 h, the solvents are removed in vacuo and the residue partitioned between water and ether. The aqueous layer is acidified with solid citric acid to approximately pH 3, then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried with MgSO4, filtered and concentrated in vacuo to yield 1.70 g (90%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2].Br[C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:1]([C:3]1[CH:4]=[C:5]([C:22]2[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=2)[CH:6]=[C:7]([F:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: N#Cc1cc(B(O)O)cc(F)c1OCc1ccccc1
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+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(F)c(OCc3ccccc3)c(C#N)c2)s1

Procedure:
(3-Cyano-4-benzyloxy-5-fluorophenyl)boronic acid and methyl 5-bromothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 2 M aqueous sodium carbonate solution and the whole was heated and refluxed for 3 hours in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 5-(3-cyano-4-benzyloxy-5-fluorophenyl)thiophene-2-carboxylate. F: 368.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].[Li]CCCC.[Cl:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[Cl:15][Si:16]([CH3:18])([CH3:17])[CH:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]([CH3:9])=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, to a solution of 48.0 g (0.393 mol) of tetramethylcyclopentadiene in 600 ml of THF, 157 ml of 2.5 M (0.393 mol) nBuLi in hexanes were added dropwise over 20 minutes at −80° C. This mixture was additionally stirred for 20 minutes at this temperature, and then for 0.5 hours at room temperature. The resulting mixture was added dropwise over 1.5 hours to a solution of 86.3 g (0.669 mol) of dichlorodimethylsilane in 150 ml of THF. The resulting mixture was stirred overnight at ambient temperature and then evaporated to dryness. Fractional distillation gave a yellow liquid, bp 52-56° C./1 mm Hg. Yield 48.3 g (57%).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][C@H:5]1[OH:13])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][C@H:4]([N:1]=[N+:2]=[N-:3])[C@H:5]([OH:13])[CH2:6]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1CCN(CCO)C[C@H]1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)OCCN1CC[C@H](N=[N+]=[N-])[C@H](O)C1
Reaction time: 10 h

Procedure:
A solution of cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol (Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and 2,6-lutidine (0.325 mL, 2.8 mmol) was treated at −20° C. dropwise with a solution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) in dichloromethane (5 mL). The temperature was allowed to reach 0° C. and kept at 0° C. for 10 hours. The resulting reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was codistilled with dry DMF (10 mL) without heating. This crude preparation of the mesylate was used without further purification directly for the next step.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][CH:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[CH:7]([CH:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][CH2:14][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[O:8]
Reactant: COC(=O)C1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=CC1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-(9H-fluoren-9-ylmethyl) 3-methyl 3,4-morpholinedicarboxylate (0.6 g, 1.633 mmol) in anhydrous toluene (80 mL) cooled to −78° C. in a dry-ice acetone bath under nitrogen was added dropwise 1.0 M diisobutylaluminium hydride in hexanes (6.53 mL, 6.53 mmol) over 4 minutes. The solution was stirred at −78° C. for 1.5 hours. The reaction was quenched at −78° C. with methanol (1.5 mL) and then aqueous HCl (1 M, 50 mL). The mixture was allowed to warm to ambient temperature and the phases separated. The aqueous was washed with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified by flash chromatography (Si) using 0-100% ethyl acetate-cyclohexane over 30 minutes. The appropriate fractions were combined and evaporated in vacuo to give the required product as a white foam, 329 mg. LCMS [LCMS4] Rt 2.43 min, m/z (ES+) 338 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (100 mg, 0.424 mmole), 4-(trifluoromethoxy)phenylboronic acid (113 mg, 0.551 mmole), CsF (129 mg, 0.847 mmole), and bis(tri-t-butylphosphine)palladium(0) (22 mg, 0.043 mmole) were combined in a screw cap vial. To this was added 1,4-dioxane (2 mL). N2 was bubbled through the mixture for 10 seconds. The vial was capped then heated to 100° C. After 6 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 0-15% EtOAc/hexanes) gave ethyl 2-[4-(trifluoromethoxy)phenyl]-1,3-thiazole-4-carboxylate (71 mg, 53%) as a pale orange solid. 1H NMR (399 MHz, CDCl3): δ 8.18 (s, 1 H); 8.07-8.03 (m, 2 H); 7.30 (d, J=8.4 Hz, 2 H); 4.46 (q, J=7.1 Hz, 2 H); 1.44 (t, J=7.1 Hz, 3 H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][CH2:16][C:17](=[O:26])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1>C(#N)C>[CH2:8]([O:15][CH2:16][C:17](=[O:26])[C:18](=[N+:36]=[N-:37])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
5,54 ml (40 mmols--2 equivalents) of triethylamine was added dropwise to a solution, cooled to 0° C., of 5,29 g (20 mmols) of tert.-butyl 4-benzyloxyacetoacetate and 4,34 g. (22 mmols) of 4-toluenesulphonyl azide in 40 ml of anhydrons acetonitrile. The mixture was stirred for 30 minutes at 0° C., treated with 8 g of Celite and evaporated in vacuo. Chromatography of the residue on 100 g of silica gel (toluene:ethyl acetate 95:5) yielded 3,98 g of the title compound as colorless crystals, melting point: 68° C., RF : 0,31 (toluene:ethyl acetate 95:5).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:7]=1.[B:14]1(B2OCC(C)(C)CO2)[O:19]CC(C)(C)C[O:15]1>>[F:13][C:5]1[CH:4]=[CH:3][C:2]([B:14]([OH:19])[OH:15])=[CH:7][C:6]=1[N:8]1[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-n1cncn1
Product: OB(O)c1ccc(F)c(-n2cncn2)c1

Procedure:
1-(5-Bromo-2-fluorophenyl)-1H-[1,2,4]triazole (1.1 g, 4.5 mmol) was reacted with bis(neopentyl glycolato)diboron (1.13 g, 5.0 mmol) using the method in Example 51 to give 4-fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid as a white solid: m/z (ES+) 208 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH2:14]>>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[C:4]([C:5]([OH:14])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: O=C1OC(=O)c2c(F)cc(F)cc21
Reactant: O
Product: O=C(O)c1cc(F)cc(F)c1C(=O)O

Procedure:
reacting said 3,5-difluorophthalic anhydride with excess water to produce 3,5-difluorophthalic acid;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C1(C)C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[O:2][CH:39]=[N:38][CH:37]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C=O)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3cnco3)c1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
(S)-5-(3-Formylphenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (380 mg, 1.07 mmol) obtained in Step 2 was dissolved in methanol (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding sodium hydroxide (120 mg, 2.14 mmol) and p-toluenesulfonylmethylisocyanide (230 mg, 1.18 mmol). After diluting the mixture with ethyl acetate, the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-9-methylthio-5-[3-(1,3-oxazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (300 mg, 71%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](=[NH:16])[O-]>C(O)C>[I:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][CH:14]([C:13]([Cl:18])([Cl:17])[Cl:12])[NH:16][C:7]2=[O:9]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N=C([O-])C(Cl)(Cl)Cl
Solvent: CCO
Product: O=C1NC(C(Cl)(Cl)Cl)Nc2ccc(I)cc21
Temperature: 45 °C

Procedure:
To a solution of 5-iodoanthranilic acid (131.5 g, 500 mmol) in ethanol (700 mL), 2,2,2-trichloroacetimidate (88.2 g, 500 mmol) was added. The reaction mixture was heated at 45° C. for 3 days under stirring. The solid formed was filtered and washed with fresh ethanol and air-dried. Yield 129.51 g (66.4%). Mp 224°-225° C. 'H-NMR (DMSO) 7.59 (d, 1 h, J=8.6 Hz), 8.21 (dd, 1H, J=2 Hz, J=7.5 Hz), 8.44, 1H, J=1.9 Hz), 13.55 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[N:10][CH:11]=[C:12]([CH:14]=[CH2:15])[CH:13]=2)[N:3]=1.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[N:10][CH:11]=[C:12]([C@@H:14]3[CH2:15][C@H:18]3[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=2)[N:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cnnc(-n2nc(C)nc2C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cnnc(-n2nc(C)nc2C)c1

Procedure:
A solution of 3-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-vinylpyridazine (23-3, 530 mg, 2.64 mmol 1.0 eq.) in toluene (35 mL) was refluxed under nitrogen. To the reaction mixture was added ethyl diazoacetate (0.50 mL, 4.75 mmol, 1.8 eq.) dropwise. The mixture was refluxed for 2 hours. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% acetone in hexanes) to afford ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarboxylate (23-4) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=2.0 Hz), 4.21 (q, 2H, J=7.2 Hz), 2.93 (s, 3H), 2.56 (m, 1H), 2.43 (s, 3H), 2.16 (m, 1H), 1.82 (m, 1H), 1.51 (m, 1H), 1.30 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=2)[N:4]=1)[CH3:2].[Br:19]Br.O>C(O)(=O)C>[Br:19][CH:1]([C:3]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccc(S(C)(=O)=O)cc2c(=O)n1C
Yield: 86.9 %

Procedure:
To a solution 2-ethyl-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (300.0 mg, 1.13 mmol) in glacial acetic acid (10 ml) cooled in an ice bath was added dropwise a solution of bromine (0.39 g, 2.26 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. Evaporated acetic acid and then water was added to the solution and the mixture was extracted with dichloromethane. The organic layer was washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×10 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% ethyl acetate in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-6-methanesulfonyl-3-methyl-3H-quinazolin-4-one (Yield 339 mg, 87.2%). 1H NMR (400 MHz, CDCl3): δ 2.13 (d, 3H, J=5.31 Hz), 3.04 (s, 3H), 3.71 (s, 3H), 5.05 (m, 1H), 7.81 (d, 1H, J=7.58 Hz), 8.16 (d, 1H, J=7.58, Hz), 8.80 (s, 1H). MS m/z calc. 343.98, found (ESI); 344.8 (M+1)+. Retention time 3.06 minutes.
Reaction SMILES: [C:1]1([CH:7]([NH2:30])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([NH:30][C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:15][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)COC(=O)Cl
Reactant: NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)NC(CCCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
2 Grams of 6-[4-(4-phenyl-4-aminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril was dissolved in 30 ml of chloroform, then to this solution was added 0.76 ml of isobutyl chloroformate at 0° C.-5° C. The reaction mixture was stirred at the same temperature for 3 hours, then concentrated. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =40:1), then converted into an oxalate by stirring with oxalic acid in acetone, and the oxalate was recrystallized from ethanol-water to yield 1.9 g of 6-[4-(4-phenyl-4-isobutoxycarbonylaminobutyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.oxalate. White powdery substance. Melting point: 221° C.-222° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:21]([F:20])=[CH:22][CH:23]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.92 (bs, 1H), 7.80 (bs, 1H), 7.60 (bd, 2H), 6.90 (m, 2H), 6.80 (bs, 1H), 6.65 (bs, 1H), 4.25 (s, 4H); LCMS: ret. time: 22.87 min.; purity: 97%; MS (m/e): 357 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][OH:33])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCCO
Product: CCN(CCO)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with 2-ethylamino-ethanol