Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]([S:19][CH3:20])=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.CS(C)=O>O>[CH3:20][S:19][C:17]1[N:16]=[C:15]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=2)[C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[N:18]=1
Reactant: CSc1nc2c(c(OS(=O)(=O)C(F)(F)F)n1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNCC2
Temperature: 100 °C
Yield: 55.4 %

Procedure:
A solution containing methylsulfanyl-4-trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester (950 mg, 2.15 mmol), 4-trifluoromethylaniline (0.6 mL, 4.74 mmol) and DMSO (8 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and diluted with water and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified (FCC; MeOH/CH2Cl2) to give the title compound (422 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([CH3:14])=[CH2:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1
Reactant: C=C(C)c1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(O)c12
Temperature: 25 °C
Reaction time: 27 h
Yield: 80.4 %

Procedure:
A mixture of 8-chloro-2-isopropenyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.26 g), ethyl acetate (10 mL), methanol (5.0 mL) and palladium hydroxide (0.05 g) was stirred at room temperature for 27 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and the filtrated concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) gave title compound as a yellow oil (0.21 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1.[OH-].[Na+]>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Reaction time: 1.5 h
Yield: 54.4 %

Procedure:
2-(Butyloxy)-8-(methoxy)-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (Isomer 2, 1.96 gm) was suspended in methanol (20 ml) and 4N HCl in dioxan (10 ml) added with stirring to give a clear solution. After 1.5 h, the solvents were evaporated to low volume and water added with stirring, followed by neutralisation with saturated sodium bicarbonate. The resulting off-white solid was filtered, washed with water and dried, yield 1.73 gm. Initial attempts to recrystallise from methanol or ethanol were unsuccessful. The recovered material was dissolved in glacial acetic acid (10 ml) with heating but precipitated immediately on addition of water (10 ml). Further addition of acetic acid (4 ml) and heating gave a clear solution, from which the product crystallised on allowing to cool. The solid was filtered, washed and dried, yield 1.06 gm (Crop 1). A second crop was obtained from the filtrate on standing, yield 460 mg, which was dissolved in sodium hydroxide and precipitated by the addition of acetic acid and then the recovered solid was heated in methanol (20 ml) with further additions of methanol (15 ml) to the boiling mixture to give a cloudy solution, which was allowed to cool. The resulting solid was filtered off, yield 257 mg. This was combined with the first batch of solid (Crop 1) and added portionwise to boiling methanol (130 ml) to give a slightly cloudy solution. On allowing to cool with stirring, a white solid crystallised out which was filtered off, washed with methanol and dried, to give the title compound yield 1.02 gm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15]2.[Cl-].[NH4+].[OH-].[Na+]>CCCCCC.C(OCC)C>[OH:22][C:16]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=2)[CH:17]2[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]2)[CH2:15]1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CN2CCC1CC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccc(Br)nc2)CN2CCC1CC2
Temperature: -67 °C
Reaction time: 0.75 h

Procedure:
27.6 g (0.116 mol) of 2,5-dibromopyridine in 1 000 ml of ethyl ether are introduced into a 2 000 ml three-necked flask, the reaction mixture is cooled to −67° C. and 56 ml (0.140 mol) of a 2.5 M solution of butyllithium in hexane are added dropwise in 10 min. The mixture is stirred at −67° C. for 45 min before adding 14.5 g (0.116 mol) of 1-azabicyclo[2.2.2]octan-3-one in solution in 150 ml of ethyl ether in 45 min, and the mixture is stirred at −67° C. for 3 h. 300 ml of a saturated aqueous solution of ammonium chloride are added followed by 200 ml of a concentrated aqueous solution of sodium hydroxide, the aqueous phase is extracted with chloroform, and the organic phases are dried and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column, eluting with a 95/5/0.5, then 80/15/1.5, mixture of chloroform, methanol and ammonia.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21](O)=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl-].C[N:26](C=O)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([NH2:26])=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Agent: [Cl-]
Solvent: ClCCl
Product: NC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (0.86 mg, 0.29 mmol) was suspended in CH2Cl2 (2 mL) and oxallyl chloride (0.038 mL, 0.4 mmol) was added followed by a drop of DMF. Mixture was stirred at room temperature for 3 h and solvent was evaporated and residue dried under vacuum. The crude acid chloride was dissolved in a solution of NH3 in dioxane and was stirred at room temperature. Solvent was evaporated, a solution of aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 and then with ethyl acetate. Residue was purified by prep plate (5% MeOH/CH2Cl2) to give the title compound as a solid. MS (ESI pos. ion) m/z: 299. (M+H). Calc'd Exact Mass for C20H14N2O: 298.
Reaction SMILES: S=[C:2]1[C:7]([C:8](OCC)=[O:9])=[N:6][N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[C:4]2[CH:25]=[CH:26][S:27][C:3]1=2.[NH2:28][NH2:29]>C(O)C>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:5]3[C:4]4[CH:25]=[CH:26][S:27][C:3]=4[C:2]4=[N:28][NH:29][C:8](=[O:9])[C:7]4=[N:6]3)=[CH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccsc2c1=S
Reactant: NN
Solvent: CCO
Product: O=c1[nH]nc2c3sccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-thioxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydrothieno[3,2-c]pyridazine-3-carboxylate (23 mg, 0.058 mmol) and hydrazine (1.0 mL, 31 mmol, 550 equiv) were combined in absolute ethanol (7 mL) and placed into an oil bath preheated to 85° C. for 2 hours. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[CH2:16]([O:18][CH:19]([O:28][CH2:29][CH3:30])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH3:17]>>[CH2:29]([O:28][CH:19]([O:18][CH2:16][CH3:17])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:8]([CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=2)=[CH:22][CH:21]=1)[CH3:30]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Cn1ccnc1CNCc1nccn1C
Product: CCOC(OCC)c1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1

Procedure:
The same procedure as in Example 3 was carried out, except that 1-(1-methyl-1H-imidazol-2-yl)-N-[(1-methyl-1H-imidazol-2-yl)methyl]methaneamine (International Publication WO 2007/058322 pamphlet, Example 58) was used in place of the compound obtained in Example 2, and 4-(diethoxymethyl)benzaldehyde (CAS Registry Number: 81172-89-6) was used in place of isobutylaldehyde in Example 3, the title compound having the following physical properties was obtained.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18]Br)[CH:9]=1.Cl>CN(C=O)C>[Br:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH2:18][O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:9]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1COCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Nail (0.5 g of 60% dispersion in oil) in DMF (10 ml) was added trifluoroethanol (0.92 ml) and the mixture stirred for 30 minutes. After this time the mixture was cooled to 0° C. and a solution of methyl 4-bromo-2-bromomethylbenzoate (3.52 g) in DMF was added, and the resultant mixture stirred at room temperature for 1 hour. 0.5M HCl was added and the mixture extracted with ether. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to yield methyl 4-bromo-2-trifluoroethoxymethylbenzoate (3.89 g) as a yellow oil, NMR (CDCl3) 3.9(s,3H), 4.0(q,2H), 5.1(s,2H), 7.5(dd,1H), 7.85(d,1H), 7.9(s,1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:49]([O:50]C(=O)C)[C@H:48]([O:54]C(=O)C)[C@@H:47]([C:58]([O:60]C)=[O:59])[O:46][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@H:20]([O:28]C(=O)C)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16](=[O:32])[N:15]2[C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]([NH:43][CH2:44][CH3:45])=[O:42])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)(=O)C.[C-]#N.[Na+]>CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[C@@H:17]([CH2:18][CH2:19][C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:28])[C:16](=[O:32])[N:15]2[C:33]2[CH:34]=[CH:35][C:36]([C:39]#[C:40][C:41]([NH:43][CH2:44][CH3:45])=[O:42])=[CH:37][CH:38]=2)=[CH:12][CH:13]=1)[C@@H:6]1[O:46][C@H:47]([C:58]([OH:60])=[O:59])[C@@H:48]([OH:54])[C@H:49]([OH:50])[C@H:5]1[OH:4]
Reactant: CCNC(=O)C#Cc1ccc(N2C(=O)[C@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)C#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-((2S,3R)-3-[(3S)-3-(acetyloxy)-3-(4-fluorophenyl)propyl]-1-{4-(3-(ethylamino)-3-oxoprop-1-yn-1-yl]phenyl}-4-oxoazetidin-2-yl)phenyl methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosiduronate (11a) (22.0 mg, 0.026 mmol) and sodium cyanide (−1 mg, 0.020 mmol) in methanol (3 mL) was heated to 45° C. After 18 h, the reaction mixture was concentrated under reduced pressure and dissolved in methanol/water/triethylamine (1:3:1, 2.5 mL). After stirring at room temperature for approximately 1 h, the volatiles were evaporated in vacuo, and the crude residue purified by preparative reversed phase high performance liquid chromatography on YMC Pack Pro C18 phase (gradient elution; 10-60% acetonitrile/water as eluent, 0.1% TFA modifier) to give the title compound (11b) m/z (ES) 663.0 (M+H)+; HRMS (ES) m/z calcd. for C35H36FN2O10 (MH+) 663.2354, found 663.2341.
Reaction SMILES: [P:1]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17]C)=[O:16])[CH:10]=1)=[O:7])([OH:4])([OH:3])=[O:2].[OH-].[Na+]>>[P:1]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=1)=[O:7])([OH:3])([OH:4])=[O:2]
Reactant: COC(=O)c1cc(NC(=O)CP(=O)(O)O)ccn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(CP(=O)(O)O)Nc1ccnc(C(=O)O)c1

Procedure:
A mixture of 377 mg of methyl 4-(α-phosphonoacetamido)-picolinate and 4.2 ml of 1N sodium hydroxide is heated at 80° for 10 minutes. The reaction mixture is cooled, filtered through Dowex 50-X8 resin and evaporated to dryness. Trituration with ethanol affords 4-(α-phosphonoacetamido)-picolinic acid, m.p. 249°-252° (dec).
Reaction SMILES: C1S(=O)(=O)CCC1.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19].N>C(Cl)Cl>[Cl:15][C:13]1[CH:14]=[C:9]([NH:19][C:18]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:17]=2[Cl:16])[N:10]=[CH:11][N:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(Cl)c(N)c1
Agent: N
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Temperature: 125 °C
Yield: 57.4 %

Procedure:
Tetramethylene sulphone (10 ml) was added to 4,6-dichloropyrimidine (25.0 g, 170 mmol) and heated to 125° C. 2-Chloro-5-methylaniline (11.90 g, 84 mmol) was added portion wise over 20 mins. The reaction mixture was heated at 125° C. for 2 hours. The reaction was allowed to cool to room temperature and DCM (200 ml) was added. The mixture was basified to pH 9-10 with methanolic ammonia and evaporated onto silica (15 g). The residue was purified by column chromatography eluting with EtOAc:isohexane (10:90) to give a white solid (12.25 g, 29%). NMR (300 MHz): 2.3 (s, 3H), 6.7 (s, 1H), 7.0 (d, 1H), 7.4 (d, 1H), 7.5 (s, 1H), 8.4 (s, 1H), 9.4 (s, 1H); m/z 254 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-methylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH:47]([C@H:50]1[CH2:55][CH2:54][C@H:53]([OH:56])[CH2:52][CH2:51]1)([CH3:49])[CH3:48]>>[Cl:17][C:18]1[C:19]([O:56][C@H:53]2[CH2:54][CH2:55][C@H:50]([CH:47]([CH3:49])[CH3:48])[CH2:51][CH2:52]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)[C@H]1CC[C@H](O)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CC(C)[C@H]1CC[C@H](Oc2cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc2Cl)CC1

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with trans-4-isopropylcyclohexanol, the title compound was obtained as a colorless solid (0.10 g, 24%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.34 (d, J=12.5 Hz, 1H), 4.53-4.43 (m, 1H), 2.87 (s, 6H), 2.11-2.07 (m, 2H), 1.75-1.71 (m, 2H), 1.50-1.20 (m, 3H), 1.24-1.07 (m, 3H), 0.86 (d, J=6.8 Hz, 6H); MS (ES−) m/z 419.1, 421.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:32][CH3:33])[CH2:4][CH2:3]1.[CH:34]1([CH:37]=O)[CH2:36][CH2:35]1.[BH4-].[Na+]>CCO>[CH:34]1([CH2:37][NH:1][C:2]2([CH2:5][O:6][C:7]3[CH:16]=[C:15]4[C:10]([C:11]([O:17][C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[C:24]([C:28]([NH:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]6)=[CH:12][CH:13]=[N:14]4)=[CH:9][C:8]=3[O:32][CH3:33])[CH2:3][CH2:4]2)[CH2:36][CH2:35]1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N)CC5)c(OC)cc34)ccc12
Reactant: O=CC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NCC6CC6)CC5)c(OC)cc34)ccc12

Procedure:
The compound of Example 3 (100 mg) was refluxed with cyclopropanecarbaldehyde (2 eq) in EtOH (8 ml) for 4 hours. To the reaction was added NaBH4 (2.2 eq), the reaction was refluxed for 20 minutes and evaporated. The residue was purified with silica gel column to give the titled product (40 mg). Mass: (M+1), 498
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15].S(=O)(=O)(O)O>C(Cl)CCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([O:10][CH2:14][CH3:15])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C

Procedure:
2-(4-hydroxyphenoxy)propionic acid (9.0 g), ethanol (15 ml) and concentrated sulfuric acid (0.5 ml) were added to ethylene dichloride (40 ml) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and the ethylene dichloride layer was separated and washed twice with water and twice with aqueous 2% NaHCO3. The organic fraction was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give the product, ethyl 2-(4-hydroxyphenoxy)-propionate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:22][C@H:9]1[N:8]([C:5]2[N:6]=[N:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[C:3]3[CH:26]=[CH:25][CH:24]=[N:23][C:4]=23)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
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+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(C(F)(F)F)cc2)c2cccnc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (180 mg, 489 μmol), tetrakis(triphenylphosphine)palladium (283 mg, 245 μmol), 4-trifluoromethylphenylboronic acid (139 mg, 734 μmol), and 2 M sodium carbonate (489 μl, 979 μmol) afforded (R)-(3-methyl-4-(5-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)piperazin-1-yl)(phenyl)methanone 84 after chromatographic purification. MS 477.2 (calc'd) 478.1 (M+H, found).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([O:9]CC1C=CC([N+]([O-])=O)=CC=1)=[O:8]>O1CCCC1.[Zn]>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1nnsc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1nnsc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
To a solution of 270 mg of 4-methyl-5-p-nitrobenzyloxycarbonyl-1,2,3-thiadiazole in 7 ml of tetrahydrofuran and 7 ml of 0.35M phoshate buffer (pH 6.1) was added 2.7 g of zinc powder, and the reaction mixture was stirred for 4 hours at room temperature. After the reaction, the reaction mixture was filtered using Celite and the filtrate was rendered alkaline by adding sodium carbonte and washed with ethyl acetate. The aqueous layer was then acidified by hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, the solvent was removed under reduced pressure. The resulting residue was purified using silica gel column chromatography to give 120 mg (91.0%) of 4-methyl-5-hydroxycarbonyl-1,2,3-thiadiazole. m.p. 190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[N:8]2)=[CH:24][CH:25]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(C2=NN(Cc3ccc(N)cc3)C(=O)CC2)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2=NN(Cc3ccc(NC(=O)c4cccnc4)cc3)C(=O)CC2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 3.4 g of 2-(4-aminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, m.p. 184°, and 0.75 ml of pyridine in 100 ml of dichloromethane is treated with 1.4 g of nicotinoyl chloride and subsequently stirred for 1 hour. The solvent is removed and the mixture is worked up in the customary manner. After recrystallization, 2-(4-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one is obtained.