Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]>C(O)C.Cl.O>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[C:5]#[CH:6]
Reactant: C#CC(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C#CC(C)(C)C(=O)CCl
Yield: 82.9 %

Procedure:
275 g (1.25 moles) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine in 1.25 liters of ethanol and 620 ml of concentrated hydrochloric acid are heated for 5 hours under reflux. The mixture is diluted with water and repeatedly extracted with n-hexane. After drying the extracts and stripping off the solvent, 176 g of crude product remain. Distillation gives 149.9 g (that is to say 83% of theory) of 1-chloro-3,3-dimethyl-pent-4-in-2-one of boiling point 67°-70° C./20 mm Hg.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:5][CH2:4]1.C[Al](C)C.C[O:11][C:12]([C:14]1[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=O.O>O1CCOCC1>[CH:3]1([CH2:2][NH:1][C:12]([C:14]2[N:15]=[N:16][C:17]([NH:20][CH2:21][C:22]3[C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:24][O:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of aminomethylcyclopropane (0.11 mL, 1.2 mmol) in dioxane (5 mL) was added dropwise trimethylaluminum solution (2 M solution in hexane, 0.62 mL, 1.24 mmol). After stirring for 1 h at room temperature a suspension of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred at 90° C. for 2 h, cooled to room temperature and poured into water. Extraction (ethyl acetate/saturated aqueous Seignette salt solution) followed by drying of the organic phase over sodium sulfate and evaporation afforded an oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (60 mg, 54%) which was obtained as a light yellow foam. MS: m/e=364.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].O>C(O)CC>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Clc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
5.0 g of 2-amino-5-iodopyridine, 5.3 g of 2-bromo-1-(4-chlorophenyl)ethanone and 2.67 g of sodium hydrogen carbonate in 150 ml of n-propanol are placed in a round-bottomed flask. The mixture is heated at 80° C. for 40 h and left to cool, and 700 ml of water are added. The precipitate is recovered by filtration, washed with water and dried under reduced pressure. 5.51 g of compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-fluoro-phenyl)-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].Cl>CN(C=O)C>[CH2:12]([O:19][C:9]1[C:8]([F:11])=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a mixture obtained by adding 5.0 g of 3,4,5-trifluorobenzonitrile and 4.5 g of benzyl alcohol to 25 ml of DMF was added 1.5 g of 60% sodium hydride (oily) at 0° C. The mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7.0 g of 4-benzyloxy-3,5-difluorobenzonitrile was obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[CH2:19][C:20]1[CH:21]=[C:22]([S:26]([CH2:34][CH3:35])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:32]([O:31][C:29]([N:28]=[S:26]([CH2:34][CH3:35])([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH:21]=1)=[O:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(CBr)c1
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Yield: 62 %

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (50 mg, 0.21 mmol) and (RS)-S-[3-(bromomethyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (108 mg, 0.32 mmol) are suspended in 5.0 mL of acetone. After addition of potassium carbonate (55 mg, 0.4 mmol), the reaction mixture is refluxed for 6 hours. The batch is diluted with ethyl acetate and the organic phase is washed with water and dried over sodium sulphate to leave, after removal of the solvent and also after chromatographic purification (silica gel, hexane/ethyl acetate: 0→100% ethyl acetate, followed by ethyl acetate/methanol: 9/1) the desired product in 62% yield (65 mg).
Reaction SMILES: CS[C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]2[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=[C:22]2[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:16][CH2:17]2)=[CH:29][CH:30]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CSc1nc2cccnc2s1
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A mixture of 2.8 parts of 2-(methylthio)thiazolo[5,4-b]pyridine and 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine was stirred for 24 hours at 140° C. The reaction mixture was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.9 parts (25%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiazolo[5,4-b]pyridin-2-amine; mp. 203.5° C. (compound 103).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Product: CC(C)(C)c1nc2cc(N3CCN(c4ccccc4)CC3)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 7 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, in 8.2 g of N-phenylpiperazine is heated at 150°-160° for 12 hours, cooled and poured into water. The paste is extracted with methylene chloride, washed with 2N HCl, then with 10% NaOH and then with water. The organic layer is dried, the solvent evaporated and the solid crystallised from isopropyl alcohol to give 2-tert-butyl-6-nitro-5-[4-phenylpiperazin-1-yl]benzothiazole, melting at 152°-155°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccccc1
Reactant: Oc1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: Fc1cc(Oc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2,5-difluorophenol (500 my, 0.002 mol), phenylboronic acid (0.73 g, 0.0060 mol), TEA (2.0 mL, 0.014 mol), cupric acetate (0.70 g, 0.0038 mol) and DCM (20 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.81 (dd, J=8.84, 7.07 Hz, 1H), 6.98-7.08 (m, 2H), 7.19 (t, J=7.45 Hz, 1H), 7.31-7.48 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]4[N:27]=[C:26]5[C:28]([Cl:32])=[C:29]([Cl:31])[S:30][C:25]5=[CH:24][CH:23]=4)[CH:15]=3)[OH:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C([O-])(O)=O.[Na+]>>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@@H:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]4[N:27]=[C:26]5[C:28]([Cl:32])=[C:29]([Cl:31])[S:30][C:25]5=[CH:24][CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[O:13][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H](CCc1ccc(C2CC2)cc1)c1cccc(C=Cc2ccc3sc(Cl)c(Cl)c3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H](CCc1ccc(C2CC2)cc1)c1cccc(C=Cc2ccc3sc(Cl)c(Cl)c3n2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the alcohol (Step 5) (230 mg, 0.47 mmol) in CHCl2 (2.5 mL) was added at -40° C. Et3N (100 μL, 0.717 mmol) and MsCl (45.0 μL, 0.574 mmo.). The resulting mixture was then warmed to 0° C. After a period of 10 min, a saturated solution of NaHCO3 was added. The mesylate was extracted with CH2C12, dried over Na2SO4, evaporated and co-distilled two times with toluene and used as such for the next step.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C)C=O.F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1ccc2c(c1)CCNC2
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (909 μl, 7.26 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 4 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (506 g, 2.42 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 3.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=10/1). Thus, 1,2,3,4-tetrahydro-2-[2-nitro-4-(trifluoromethyl)phenyl]isoquinoline (779 mg, 99.9%) was yielded as an orange-colored solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2
Reactant: COc1ccc2[nH]c(C)cc2c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol) in methylene chloride (9 ml) cooled at −30° C. was added a solution of boron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml). After stirring for 1 hour at ambient temperature, the mixture was poured onto water and was diluted with methylene chloride. The pH of the aqueous layer was adjusted to 6. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[C:44]([OH:46])=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)CC)C.[C:54]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>C(#N)C>[C:57]([O:56][C:54]([N:61]1[CH2:66][CH2:65][N:64]([C:44]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][N:38]2[C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[O:46])[CH2:63][CH2:62]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1CCCCN1C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2C(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
26.6 g of BOP, 13.6 g of 1-(carbobenzyloxy)-2-piperidinecarboxylic acid and then 11.9 ml of triethylamine are added, at 0° C., to a solution of 8 g of 1-Boc-piperazine in 80 ml of acetonitrile. The medium is stirred at AT for 12 hours and then concentrated. The medium is taken up in EtOAc, and washed three times with a saturated Na2CO3 solution and then with a saturated NaCl solution. After drying over MgSO4 and evaporation, 35.45 g of reaction crude are recovered. It is taken up in DCM and then washed twice with 5M sodium hydroxide, and with a saturated NaCl solution, and then dried over MgSO4. After evaporation, the solid is triturated in TBME, filtered, rinsed with TBME, and then dried, to give 17.93 g of the desired compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH2:10]([NH2:13])[CH2:11][CH3:12]>>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:13][CH2:10][CH2:11][CH3:12])[N:3]=[N:4][CH:5]=1
Reactant: Nc1c(Cl)cnnc1Cl
Reactant: CCCN
Product: CCCNc1nncc(Cl)c1N
Temperature: 125 °C
Yield: 35 %

Procedure:
A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 2 g, 12.3 mmol) and 70% aqueous propylamine (8 mL) was heated at 125° C. in an autoclave vessel for 5 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 35% yield, 800 mg.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=[O:2].[CH3:30]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:30][O:2][C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Reaction time: 2 h

Procedure:
To a solution of the carboxylic acid from Example 33 (0.080 g, 0.20 mmol) under a nitrogen atmosphere in dichloromethane (25 ml) at 0° C. were added DMF (20 □l) and oxalyl chloride (31 mg, 0.24 mmol). The mixture was stirred at 0° C. to room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in methanol (4 ml) and dichloromethane (16 ml) and the mixture stirred at room temperature for 16 h. The mixture was then washed with 1M KHSO4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol 96:4) to give a white solid; yield 0.049 g (60%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH:24][C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(NC(N)=O)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)Cc2ccccc2)cc1-c1cccc(NC(N)=O)c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-N-(2-phenylacetyl)-3′-ureido-biphenyl-3-sulfonamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].[CH3:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:17]([CH3:18])=[C:13]([CH3:12])[C:14]([CH3:15])=[N:11]1
Reactant: COc1ccccc1NN
Reactant: CC(=O)C(C)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-n1nc(C)c(C)c1C

Procedure:
200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 4 ml of ethanol, and 134 μl of 3-methyl-2,4-pentanedione was added and heated at reflux for 3 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 209.8 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH3:28])[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-c2cc(N(C)c3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenylamino)pyrimidine (1.0 g) in N,N-dimethylformamide (15 ml) were added potassium tert-butoxide (0.37 g) and methyl iodide (0.34 ml), and the mixture was stirred at ambient temperature for 1.5 hours. Then the mixture was poured into ice-water (200 ml) and stirred for an hour. The precipitates were collected, washed with water, dried in the air, and recrystallized from ethanol to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-[N-methyl-N-(2,4,6-trimethylphenyl)amino]pyrimidine (0.58 g).
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.O1CCCC1.[H][H]>C(O)C>[CH2:2]([C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(CC(=O)OCC)C(=O)OCC
Yield: 45 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 10 bar together with 1100 ml of tetrahydrofuran and 60 g of catalyst G (4-mm tablets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 193 g (45%) of triethyl propane-1,2,3-tricarboxylate.
Reaction SMILES: [Br:1]Br.[NH:3]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[N:14][C:4]1=2>C(O)(=O)C.C(Cl)Cl>[Br:1][C:12]1[CH:13]=[N:14][C:4]2[NH:3][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:11]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)CNCCCN2
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CNCCCN2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Bromine (33 μL, 0.63 mmol) was added to a solution of 1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocine (69 mg, 0.42 mmol) in 5 mL of acetic acid and stirred at room temperature for 19 h. Dilute with DCM and wash with saturated NaHCO3, wash the organic layer with brine, separate, dry over MgSO4, and concentrate in vacuo to obtain orange solid product. Yield 91 mg (90%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.54 (s, 1H), 4.44 (s, 2H), 3.68 (s, 2H), 3.33 (m, 2H), 2.05 (m, 2H); ESI MS m/z 242, 244 [C9H12N3Br+H]+
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([C:37]([OH:38])=[O:40])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[C:7]=1[CH3:19]
Reactant: C=CCc1c(O)c(Cl)c(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)c2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (6.4 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.6 g of 4-chloro-1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 284°-287° C. This compound showed a mass spectrum having a molecualr ion peak at m/e 330.