Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([CH2:19][C:20]([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c[nH]c(C(=O)Cc2ccccc2)c1
Reaction time: 3 h
Yield: 5 %

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (920 mg., 7 mmoles) was dissolved in 25 ml. of methylene chloride. Phenylacetyl chloride (930 mg., 6 mmoles) was added and dissolved. Finally, stannic chloride (1.2 ml., 12 mmoles) was added. The reaction mixture was stirred for 3 hours, water (15 ml.) added dropwise, diluted with 50 ml. of ether, the organic phase separated, washed with 20 ml. of water and evaporated to dryness to yield methyl 5-phenylacetylpyrrole-3-carboxylate (semisolid, Rf 0.3 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant). The entire batch was employed without weight determination in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[OH:31])[CH:26]=[O:27])([CH3:22])[CH3:21].O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:20]([C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[C:30]=1[O:31][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[CH:26]=[O:27])([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
Triphenylphosphine (5.14 g, 19.58 mmol) was added to a solution of 3,5-diisopropyl-4-hydroxybenzaldehyde (4 g, 19.58 mmol) in tetrahydrofuran (40 ml) followed by addition of 2-hydroxyethylmorpholine (2.57 g, 19.58 mmol) and then the dropwise addition of diethylazodicarboxylate (3.41 g, 19.58 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure and partitioned between 2N hydrochloric acid (200 ml) and ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (2×150 ml), basified to pH 9 with solid sodium bicarbonate and extracted with ethyl acetate (3×150 ml). The organic layers were combined, dried over magnesium sulfate and concentrated to afford 900 mg (14%) of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cccnc1CBr
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.291 g (23.921 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 8.573 g (26.313 mmol) of caesium carbonate were put in DMF (10 ml) and then 5.00 g (26.313 mmol) of 2-(bromomethyl)-3-fluoropyridine dissolved in DMF (20 ml) was added dropwise. The mixture was stirred overnight at RT. Then it was left to cool and was poured into 200 ml water. A precipitate was filtered off with suction, it was washed with water and dried overnight under high vacuum. 6.28 g (70% of theor.) of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1([F:17])[CH2:14][CH:13]1[CH2:15][OH:16]>>[F:11][C:12]1([F:17])[CH2:14][CH:13]1[CH2:15][O:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC1CC1(F)F
Product: O=C(O)c1ccc(OCC2CC2(F)F)nc1

Procedure:
Using 6-chloronicotinic acid and 2,2-difluorocyclopropanemethanol, and in the same manner as in Step A of Example 40, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].CC(O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(CC[N+](=O)[O-])cc1OC

Procedure:
The nitrostyrene derivative (3) is then cooled to about -10°-10° C., treated with silica gel, and reduced using 1.5-4 equivalents of a boron-based reducing agent, e.g., sodium borohydride, with 2-propanol and an inert solvent, e.g., CH2Cl2, at -10°-10° C. for 20-60 minutes to produce a nitrophenylethane derivative of formula 4 (step 2). For example, 3,4-dimethoxy-β-nitrostyrene (3) is treated with 2-propanol and SiO2 in CH2Cl2 at 0°-10° C. for 20 minutes, followed by reduction with 1.5 eq NaBH4 at 5° C. for 30 minutes to yield 2-(3,4-dimethoxyphenyl)nitroethane (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=[C:31]([CH3:39])[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)c2ccccc2n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)nc5ccccc45)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
75 mg (0.27 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.26 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-quinoline and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>CCOCCO>[C:12]([NH:20][N:21]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([OH:1])[CH3:11])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1
Reactant: CC(O)C(=O)c1ccccc1
Reactant: NNC(=O)c1cccnc1
Solvent: CCOCCO
Product: CC(O)C(=NNC(=O)c1cccnc1)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 15.0 g of 2-hydroxypropiophenone and 13.7 g of nicotinic acid hydrazide is stirred in 100 ml of ethyl cellosolve, initially for 18 hours at 120° C. (with distillation of a small amount of solvent) and then for a further 5 hours at room temperature. The light yellow precipitate produced is isolated by suction filtration and washed with ethanol and then with water. 18.5 g of 2-hydroxypropiophenone nicotinoylhydrazone are obtained after the product has been dried at 40°-50° C. under vacuum. 2.7 g of this product are suspended in 30 ml of dimethylformamide and treated with a solution of 2.8 g of nickel(II) acetate·4H2O in 35 ml of dimethylformamide. The resulting mixture is stirred at 120° C. for 4 hours and the product is then isolated by filtration and subsequently washed with isopropanol and then with water. After the product has been dried under vacuum at 60°-70° C., 2.8 g of a yellow powder of the following formula (or a tautomeric form thereof): ##STR17## as the 1:1 nickel complex are obtained which gives the following microanalysis:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(CO)cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
12.67 g (14.6. mmol) of manganese dioxide were added to a solution of 3.45 g (7.35 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-hydroxymethyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 61) in 40 ml of methylene chloride, and the resulting mixture was vigorously stirred at room temperature for 10 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure to give the title compound as a foam-like substance in a 86% yield.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][O:28][CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: COCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: COCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and methoxyacetic acid, the title compound was obtained in 91% purity by HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8]
Reactant: COc1cccc(Cl)c1B(O)O
Reactant: Clc1ccccc1Br
Solvent: O
Solvent: COCCOC
Product: COc1cccc(Cl)c1-c1ccccc1Cl
Yield: 73.7 %

Procedure:
Treatment of 2-bromochlorobenzene (15.5 g, 80.6 mmol) with 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (74%) of 2.2′-dichloro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:39])[CH2:35][C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)=[CH:6][N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of the amino compound 120 (400 mg, 1.08 mmol) in DMF (10 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (444 mg, 2.25 mmol), EDC (519 mg, 2.70 mmol) was added HOBT (364 mg, 2.70 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 117 (348 mg, 58% yield) as a white solid. 1H NMR (DMSO-d6). δ ppm: 10.58 (s, 1H), 10.06 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.10-7.76 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.88 (dd, J=2.4 and 13.2 Hz, 1H), 7.74 (s, 1H)), 7.51 (t, J=8.8 Hz, 1H), 7.43 (dd, J=1.6 and 8.8 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.21-7.14 (m, 2H), 6.66 (d, J=5.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.34 (t, J=7.2 Hz, 3H). MS (m/z): 534.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:6]=2[CH:22]=1.[Cl:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:24][Cl:23])[CH2:9][N:8]=[C:7]([C:14]3[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=3[F:20])[C:6]=2[CH:22]=1
Reactant: O=C(CCl)CCCCO
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Solvent: C1CCOC1
Product: OCCCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-6-hydroxy-2-hexanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(4-hydroxybutyl)ethylidene]hydrazino]-5-(2,6-difluoropheny1)-3H-1,4-benzodiazepine.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.C([O-])(=O)C.[Na+].C(O)C.Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>O>[C:21]([N:25]1[CH:4]=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:26]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1ccc(C(F)(F)F)n1
Yield: 52.5 %

Procedure:
To a mixture of 5 g of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one, 3 g of sodium acetate and 15 ml of ethanol was added 4.6 g of tert-butylhydrazine hydrochloride, and the mixture was heated to reflux for 2 days. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.0 g of 1-tert-butyl-3-trifluoromethyl-1H-pyrazole of the formula:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]([C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=2)[N:28]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([C:32]([F:33])([F:35])[F:34])=[N:30][N:31]=4)[N:28]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(6-chloronaphthalen-2-yl)sulfonylpiperazine hydrochloride and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(6-chloronaphthalen-2-yl)sulfonylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[O:19][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])([CH2:10][CH2:9]2)[CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C=C1CCC(O)(c2ccc(Br)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 50 °C
Reaction time: 24 h
Yield: 33.9 %

Procedure:
To a solution of methyl 2-(4-(4-bromophenyl)-4-hydroxycyclohexylidene)acetate (190 mg, 0.58 mmol) in acetonitrile (7 mL) was added Cs2CO3 (381 mg, 1.17 mmol) and the reaction was let stir in a 50° C. oil bath for 24 h. The resulting reaction mixture was diluted with ethyl acetate and washed with water, followed by a saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 188 mg of crude orange film. The crude material was purified by column chromatography (24 g silica gel, 0-40% EtOAc:Hept, monitor 230 nm) to afford 64 mg (34%) of the title compound as a colorless film that solidified upon standing. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.56-1.81 (m, 4H), 1.85-1.97 (m, 2H), 2.14 (td, J=9.9, 3.9 Hz, 2H), 2.92 (s, 2H), 3.63 (s, 3H), 7.32 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ ppm 170.3, 142.0, 130.9, 127.1, 119.8, 86.0, 83.2, 51.3, 37.6, 35.4 (additional signal likely hidden under DMSO solvent signal). ESI-MS m/z: 327.0 [M+H]+, retention time 1.55 min (condition E).
Reaction SMILES: [CH3:1][C@:2]12[C:10](=[O:11])[CH2:9][C@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[Br:12]Br.Br>C(O)C>[CH3:8][C:6]1([CH3:7])[C:2]2([CH3:1])[C:10]([CH:9]([Br:12])[CH:5]1[CH2:4][CH2:3]2)=[O:11]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Reactant: BrBr
Agent: Br
Solvent: CCO
Product: CC12CCC(C(Br)C1=O)C2(C)C
Reaction time: 3 h

Procedure:
D-camphor ([a]D20 -44.0°, c=7.5), in ethanol is prepared as follows Bromine (320 g) is added dropwise to d-camphor (304 g) at 80° C. over a period of three hours under stirring and the liquified reaction mixture is kept at the same condition for 3 hours. After hydrogen bromide is released by bubbling, the reaction mixture is poured into ice water (3 liters) and the resulting precipitate is recrystallized from ethanol (230 mol) to give d-3-bromocamphor (302 g), mp 76° C. [a]D20 -134° (c=10, EtOH). d-3-bromocamphor (231 g) is dissolved in chloroform (400 ml) and chlorosulfonic acid (233 g) are added dropwise to this solution over 1 hour at 50° C. The reaction mixture is refluxed for 12 hours and poured into iced water (1 liter). The layer and washings are neutralized with Ca(OH)2 (120 g), and precipitated CaSO4 is filtered off. To the filtrate (NH4)2CO3 (128 g) are added and the precipitated CaCO2 is removed. The filtrate is concentrated and crystallized crude ammonium d-bromocamphor sulfonic acid (152 g) is recrystallized from water (270 ml) to give ammonium d-bromocamphor sulfonic acid (102 g), mp. 270°-272° C.(dec), [a]D20 -85.3° (c=2, water), lit.[a]D22 -85.3° (c=4, water), [a]D20 -84.5° (c=1.6, water). Calculated for NH4C10H14O2 4SBr: C, 36.59: H, 5.53: N, 4.27. Ammonium d-bromocamphor sulfonic acid obtained above is passed through Amberlite IR-120, and the effluent is concentrated to dryness and used as free d-bromocamphor sulfonic acid monohydrate. Analysis: All samples are dried overnight in vacuo at 40° C. Melting points are measured with a Yamato MP-21 melting point apparatus in an unsealed capillary tube and are uncorrected. Optical rotations are measured with a Perkin-Elmer 141 automatic polarimeter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][C:31]([CH3:36])([CH2:34][OH:35])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][C:31]([CH2:34][OH:35])([CH3:36])[CH2:32][OH:33])[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)Nc1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
The product of Example 47, and 2-amino-2-methylpropane 1,3-diol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.01 (s, 3H), 3.43 (m, 2H), 3.62 (m, 2H), 6.03 (br s, 1H), 6.41 (d, 1H, J=9.6 Hz), 7.27-7.65 (m, 9H). LC MS (m/e)=471 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([S:15][CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:14]
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Reactant: CC(O)=S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CCSC(C)=O)S(=O)(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5.0 g (19.2 mmol) of 4-bromo-1-methoxy-1-oxobutane-2-sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed at 70° C. for 1 hr, evaporated and co-evaporated with 3×100 ml of water after being neutralized to pH 7 with NaHCO3. The mixture was redissolved in methanol, filtered through celite, concentrated and purified with SiO2 chromatography eluted with CH3OH/CH2Cl2/HCOOH 37.5:250:1 to 50:250:1) to afford 4.4 g (90% yield) of the title compound. 1H NMR (D2O) 3.95 (dd, 1H, J=4.1, 10.3 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 3.22 (dd, 2H, J=7.4, 14.9 Hz), 2.39 (s, 3H); 13C NMR 203.88, 172.91, 67.32, 56.17, 29.04, 20.61; MS m/z−254.8 (M−H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of tetrahydropyran-2-methanol (2 g, 17.2 mmol) cooled at 0° C. is added toluene-4-sulfonyl chloride (3.6 g, 18.92 mmol), followed by (2.63 mL , 18.92 mmol) of triethylamine. The mixture is allowed to reach RT and stirred overnight. Then poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9. MS (LC-MS): 271.1 [M+H]+, tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 5.32 min.