Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.[CH:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=1)=[O:7]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: CC(C)c1cccc(N)c1
Product: Cc1cc(Br)cc(C(=O)Nc2cccc(C(C)C)c2)c1
Yield: 99 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-5-methylbenzoic acid (400 mg) and 3-isopropylaniline were converted to the title compound (615 mg, 99%).
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[NH:28][C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:39](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[N:28]([CH3:39])[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:35][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: COC(=O)C(=O)N(C)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of methyl N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (compound of Example 6 (4); 3.0 g, 5.982 mmol), methyl iodide (9.387 g, 66.180 mmol), potassium carbonate (2.480 g, 17.946 mmol), 18-crown-6 (158 mg, 0.598 mmol) and acetonitrile (50 ml) was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (3.066 g, 99.4%) as a colorless oil.
Reaction SMILES: ClC1C=C(N[C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])C=CC=1SC1N(C)C=CN=1.N1(CCN2CCNCC2)C=CN=C1>CN1CCCC1=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Agent: c1cn(CCN2CCNCC2)cn1
Solvent: CN1CCCC1=O
Product: COc1ccc2ncc(C#N)cc2c1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 220 mg (0.5 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 290 mg (1.6 mmol) of 1-(2-imidazole-1-yl-ethyl)piperazine in 1.2 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 20 hours to yield the crude product. Purification by silica gel chromatography (gradient 95:5-methylene chloride/methanol to 85:15 methylene chloride/methanol) gives 210 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-{4-[2-1H-imidazole-1-yl)ethyl]piperazin-1-yl}-6-methoxyquinoline-3-carbonitrile as a beige solid, mp 251-253° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([Br:22])[C:18]([F:21])([F:19])[F:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)c(NN=C(Br)C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
3.7 g of trifluoroacetaldehyde {2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone was dissolved in 50 ml of N,N-dimethylformamide, and 2.0 g of N-bromosuccinimide was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.4 g of N-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}trifluoroacetohydrazonoyl bromide.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:36]=[CH:35][C:6]([C:7]([CH2:9][NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:15][CH2:14]2)=[O:8])=[C:5]([O:37][CH3:38])[CH:4]=1.CS(C)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:2]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([CH2:9][NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:15][CH2:14]2)=[O:8])=[C:5]([O:37][CH3:38])[CH:4]=1)=[O:1]
Reactant: COc1cc(CO)ccc1C(=O)CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C=O)ccc1C(=O)CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-hydroxymethyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-yl ester (78 mg, 1.5 mmol; prepared as described in Preparation 20) in DCM (2.5 mL) at −15° C. was added DMSO (130 μL, 22.5 mmol), and DIPEA (130 μL, 7.5 mmol). To the solution was added sulfur trioxide-pyridine complex (240 mg, 15 mmol). After 30 minutes, the reaction mixture was quenched with water (˜3 mL). Two layers were separated, the organic layer was dried over MgSO4, filtered and the title intermediate was used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]#[C:8][Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C#C)C=CC=CC=1.[CH3:23][Si:24]([CH3:27])(Cl)[Cl:25]>CCCCCC.C(OCC)C>[C:1]1([C:7]#[C:8][Si:24]([CH3:27])([CH3:23])[Cl:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C#Cc1ccccc1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C#Cc1ccccc1
Product: C[Si](C)(Cl)C#Cc1ccccc1

Procedure:
A suspension of phenylethynyllithium was prepared by the dropwise addition over 1 hour of 16 parts of a 1.0 mol/L solution of n-butyllithium in hexane to 23 parts of phenylacetylene dissolved in 100 parts of ethyl ether. This suspension was gradually added dropwise over a period of 1 hour to a mixture of 60 parts dimethyldichlorosilane and 100 parts ether. After removal of the lithium chloride by filtration, distillation of the filtrate yielded 30 parts phenylethynyldimethylchlorosilane.
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1)(=O)C>>[C:1]([O:6][C:7]12[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][C:9]([OH:17])([CH2:15]3)[CH2:8]1)[CH2:16]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:26]([C:25]1[CH:28]=[CH:29][CH:22]=[CH:23][C:24]=1[OH:5])=[CH2:27]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Product: C=Cc1ccccc1O

Procedure:
3-Hydroxyadamantyl methacrylate and 4-acetoxystyrene were charged at a charge ratio of 2:8 to synthesize a base resin. The resin obtained was treated with an alkali solution to cause soluvolysis of the acetyl group, thereby obtaining a 3-hydroxyadamantyl methacrylate-vinylphenol copolymer (molecular weight: 4,500). To polyvinylphenol produced by Maruzen Sekiyu, 15 wt % of the copolymer obtained was added and the mixture was dissolved in PGMEA (propylene glycol methyl ether acetate). To this solution, 5 wt % of triphenylsulfoium trifluoromethanesulfonate was added and thoroughly dissolved. The thus-obtained resist solution was filtered through a 0.2 μm teflon membrane filter, spin-coated on a silicon substrate subjected to an HMDS treatment, and pre-baked at 110° C. for 60 seconds to form a 0.5 μm-thick resist film. This resist film was exposed by a KrF excimer laser stepper (NA=0.45), baked at 120° C. for 60 seconds, developed with a 2.38% tetramethylammonium hydroxide (TMAH) developer, and rinsed with deionized water. With an exposure amount of 12.0 mJ/cm2, a resolution of 0.25 μmL/S was obtained. In this resist pattern, swelling was not generated.
Reaction SMILES: [NH3:1].[F:2][C:3]1[N:8]=[C:7]([C:9](=[NH:11])[O-])[C:6](=[O:12])[NH:5][CH:4]=1>C(O)C>[F:2][C:3]1[N:8]=[C:7]([C:9](=[NH:1])[NH2:11])[C:6](=[O:12])[NH:5][CH:4]=1
Reactant: N
Reactant: N=C([O-])c1nc(F)c[nH]c1=O
Solvent: CCO
Product: N=C(N)c1nc(F)c[nH]c1=O
Temperature: 0 °C
Reaction time: 17 h

Procedure:
At an ice-cooled temperature, gaseous ammonia was introduced into 2.0 mL of ethanol to prepare a saturated solution, and then 0.10 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidoate and 2.0 mL of ethanol were added. After elevating the temperature to room temperature, the mixture was left to stand for 17 hours. The deposited solid product was collected by filtration and washed with ethanol. The residue thus obtained was purified by silica gel column chromatography [eluent: chloroform:methanol=10:1], ethanol was added to the purified product, and the solid product was collected by filtration. Thus, 20 mg of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidamide was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 61.8 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 232 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (122 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].CCO>C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])=[CH:12][CH:11]=1)=[C:15]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)[C:16]([CH3:26])=[CH:17]2
Reactant: CCOC(=O)C=Cc1ccc(Oc2c(-c3ccsc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(C=CC(=O)O)cc3)c(-c3ccsc3)c(C)cc2c1
Temperature: 60 °C
Yield: 98.4 %

Procedure:
A solution containing 3-[4-(6-Methoxy-3-methyl-2-thiophen-3-yl-naphthalen-1-yloxy)-phenyl]-acrylic acid ethyl ester (201) (0.27 g, 0.61 mmol), 1 N NaOH (5 mL), EtOH (4 mL), THF (4 mL) was heated at 60° C. for 2.5 h. Reaction mixture was cooled to room temperature and quenched with 20% HCl then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified with 1.5% to 3.5% MeOH in DCM over 30 min to give 0.25 g (99%) of the title compound (202) as a white foam. 1H NMR (400 MHz, d-CDCl3): δ 2.31 (s, 3H), 3.92 (s, 3H), 6.24 (d, J=16 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 6.90-6.92 (m, 1H), 7.02-7.05 (m, 2H), 7.12 (m, 1H), 7.21-7.23 (m, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.56 (m, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[O:14][C:7]2=[C:8]([O:12][CH3:13])[N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[C:1]([C:4]1[O:14][C:7]2=[C:8]([O:12][CH3:13])[N:9]=[CH:10][C:11]([Br:15])=[C:6]2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nccc2cc(C(C)=O)oc12
Solvent: CC#N
Product: COc1ncc(Br)c2cc(C(C)=O)oc12
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A solution of 2-acetyl-7-methoxyfuro[2,3-c]pyridine (1.1 g) in acetonitrile (50 ml) was stirred at room temperature. N-Bromosuccinimide (1.0 g) was added and stirring continued overnight. The reaction was quenched by the addition of water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 33% ethyl acetate in hexane gave the title compound (1.4 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:46])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][C:39]=1[CH3:45])([CH3:36])[CH3:35])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:46])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:40][C:39]=1[CH3:45])([CH3:35])[CH3:36])[CH3:31]
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1C
Temperature: 65 °C
Yield: 92.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (0.100 g, 0.239 mmole) and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.063 g, 0.262 mmole) in anhydrous DMF (2.0 mL), is added cesium carbonate (0.093 g, 0.287 mmole). After heating at 65° C. for about 16 hours, the reaction mixture is partitioned between ethyl acetate (5 ml) and 1.0 N HCl aq. (5 ml), the aqueous layer is extracted with more ethyl acetate (2×5 ml). The combined organic layer is washed with brine (3×5 ml). The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography using silica gel (0-40% acetone/hexane) produces a colorless oil (0.107 g, 91%). Mass [EI+] 485 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[C:11]([CH3:23])[N:10]=2)=[CH:5][CH:4]=1.[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:24][CH2:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=1
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(C)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)nc(CBr)n2)cc1
Temperature: 75 °C

Procedure:
4,6-Bis-(4-methoxy-phenyl)-2-methyl-pyrimidine 23 (0.21 g, 0.7 mmol) is dissolved in 4 mL carbon tetrachloride. N-Bromo-succinimide (0.10 g, 0.56 mmol) is added and the mixture is heated to 75° C. with stirring. Solid 2,2′-azobisisobutyronitrile (AIBN) (0.01 g, 0.06 mmol) is added and the mixture is stirred at 75° C. for 24 hours. Cooling, diluting with dichloromethane, washing with water, saturated aqueous NaHCO3, and brine, followed by drying over solid Na2SO4 and concentration yielded 2-bromomethyl-4,6-bis-(4-methoxy-phenyl)-pyrimidine 24 as an oil. It is used without further purification in the next step. 1H-NMR (400 MHz, CDCl3) δ=8.02 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 6.94 (d, J=8.8 Hz, 2H), 3.82 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:22][CH:23]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: OC1CCC(Nc2ccc3ncc(-c4cccc(C(F)(F)F)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 14.3 %

Procedure:
To a solution of 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (220 mg, 0.739 mmol) and trans-4-aminocyclohexanol hydrogenchloride (85 mg, 0.739 mmol) in NMP (2.0 mL) was added NaHCO3 (79 mg, 0.739 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-trifluoromethylphenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (40 mg, 0.106 mmol, 14%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]=2[CH2:21]Br)=[O:15])=[CH:6][CH:5]=1.[CH3:28][NH:29][CH3:30].O1CCCC1>ClC1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]=2[CH2:21][N:29]([CH3:30])[CH3:28])=[O:15])=[CH:6][CH:5]=1
Reactant: CNC
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CBr)cc1
Solvent: ClCCl
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CN(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}-benzoic acid methyl ester (0.340 mol) in chlorobenzene (200 ml) and dichloromethane (800 ml) was added dropwise to a 0-5° C. solution of 2M dimethylamine in tetrahydrofuran (510 ml, 1.022 mol) over 30 minutes with the temperature below 20° C. The resulting mixture was stirred for one hour and allowed to warm to ambient temperature. After completion of reaction, the reaction mixture was washed with 5% potassium carbonate and water. Solvent was distilled at atmospheric pressure until the pot temperature reached 100° C. After cooling to ˜50° C., acetonitrile (400 ml) and ethyl Acetate (400 ml) were added to the pot. The reaction mixture was heated to reflux until all solids dissolved. The reaction mixture was allowed to cool to give 4-{2-[(3-dimethylaminomethyl-benzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester (76.6 g) as an off white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11](O)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](OCC)=[O:13].Cl.[NH2:25][NH2:26]>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:26]=[N:25][C:12]([OH:13])=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=1
Reactant: CCOC(=O)C(O)(CC(=O)c1cccc(F)c1F)C(=O)OCC
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(F)c2F)nnc1O

Procedure:
Diethyl 2-[2-(2,3-difluorophenyl)-2-oxoethyl]-2-hydroxymalonate (18.50 g, 56.1 mmol) and hydrazine monohydrochloride (4.03 g, 58.8 mmol) were stirred at reflux in ethanol (300 mL) for 96 h, and then evaporated to dryness to afford the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[O:8]1[C:4]([C:1](=[O:3])[CH:2]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cc2ccccc2o1
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1cc2ccccc2o1

Procedure:
8 g of 2-acetyl benzo[b]furan and 6 g of benzaldehyde are heated to boiling in 50 ml of methanol in the presence of 3 of concentrated hydrochloric acid. The batch is cooled after 10 h, and the precipitated yellow mass of crystals is filtered off by suction and rewashed with a small quantity of cold methanol.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1.NC1C=C(O)C(C)=CC=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17]([NH:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=3)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Product: COc1ccc(Sc2ccc(C(=O)Nc3cccc(OC)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with m-anisidine according to the procedure from Example 137C substituting m-anisidine for 5-amino-o-cresol to provide the title compound as an off white solid after silica gel chromatography (60 mg, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 3.17-3.29 (m, 1H), 3.74 (s, 3H), 3.77 (s, 3H), 6.68 (dd, J=8.09, 1.84 Hz, 1H), 6.92-6.98 (m, 1H), 6.99 (d, J=8.82 Hz, 2H), 7.24 (t, J=8.09 Hz, 1H), 7.31-7.50 (m, 5H), 7.68 (d, J=8.09 Hz, 1H), 7.79 (d, J=7.35 Hz, 1H), 7.96 (s, 1H), 8.61 (s, 1H), 8.89 (d, J=8.09 Hz, 1H), 10.18 (s, 1H); MS (APCI) m/z 552 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:11]3[N:16]=[N:15][CH:14]=[CH:13][CH:12]=3)=[C:7]([CH3:17])[C:6]=2[CH:18]=1.Cl.[O:20]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:11]3[CH:12]=[CH:13][C:14](=[O:20])[NH:15][N:16]=3)=[C:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1c(Sc2cccnn2)oc2ccc(Cl)cc12
Reactant: C1COCCO1
Agent: Cl
Product: Cc1c(Sc2ccc(=O)[nH]n2)oc2ccc(Cl)cc12
Yield: 73 %

Procedure:
A mixture of 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-pyridazine (1.6 mmol, 500 mg), conc. HCl (1 mL), and dioxane (5 mL) was heated at 1000C for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue, and the resulting white precipitate was collected and crystallized from ethanol to obtain the desired product, 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-2-H-pyridazin-3-one (73%, 113 mg); mp>240° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH:21]=[CH:20][CH:19]=[N:18]1.[OH-].[Na+]>CS(C)=O>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cccn2)cc1N1CCCCC1
Yield: 85.4 %

Procedure:
Using a procedure similar to Example 4, step (a), a solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (98 mg, 0.43 mmol, as prepared in Example 5, step (a)), pyrazole (67.8 mg, 0.600 mmol), and NaOH (22.4 mg, 0.560 mmol) were heated in 3 mL of DMSO overnight to afford 100 mg (85%) the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C14H16N4O2, 273.1 (M+H), found 273.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1)#[N:2].[ClH:10]>C(O)C.[Pd]>[ClH:10].[ClH:10].[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[N:4]=1
Reactant: N#Cc1cccc(F)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1cccc(F)n1
Yield: 72.7 %

Procedure:
Dissolve 2-cyano-6-fluoropyridine (300 mg, 2.46 mmol) in absolute ethanol (12 mL). Add 10% Pd/C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol). Hydrogenate at 40 psi overnight. Filter through Celite® and concentrate to give the title compound as a solid (356 mg, 73%). MS (ES+) m/z: 127 (M+H)+.