Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[CH3:27])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Temperature: 60 °C
Yield: 100 %

Procedure:
To 2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9 mg, 0.018 mmol) and potassium carbonate (25.4 mg, 0.184 mmol) in acetone (0.1 ml) is added iodomethane (0.115 ml, 1.840 mmol). After heating at 60° C. for 1 day, the reaction mixture is filtered and concentrated to dryness to afford 2-(4-Fluoro-phenyl)-5-iodo-6-(methanesulfonyl-methyl-amino)-furo[2,3-b]pyridine-3-carboxylic acid methylamide (9.3 mg, 0.018 mmol, 100% yield). MS (ESI) m/z 503.9 (M+1). 1H NMR (400 MHz, CD3CN) δ ppm 8.60 (s, 1H), 7.95 (m, 2H), 7.23-7.18 (m, 2H), 6.79 (br s, 1H), 3.14 (s, 3H), 2.80-2.79 (d, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(CO)cc1
Reaction time: 18 h
Yield: 35.9 %

Procedure:
A mixture of 4-hydroxybenzylalcohol (1.52 g, 12.2 mmol.), allyl bromide (1.1 ml, 12.2 mmol.), acetonitrile (40 ml), and potassium carbonate (2.54 g, 18.4 mmol.) was reluxed for 18 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4) and evaporated to give the product as a yellow oil (0.72 g, 71%). 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 1H), 4.55 (m, 2H), 4.6 (s, 2H), 5.3 (d, 1H, J=11.5 Hz), 5.43 (d, 1H, J=16.5 Hz), 6.1 (m, 1H), 6.94 (m, 2H), 7.33 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 65.3, 69.2, 115.2, 118.1, 129.0, 129.4, 133.7, 158.6.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)ccc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.011 g of product in 46% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20](O)=[O:21])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH2:67]([CH2:69][NH2:70])[OH:68]>CN(C=O)C>[OH:68][CH2:67][CH2:69][NH:70][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:28][CH:27]=3)=[N:10][C:11]=2[CH:17]=1
Reactant: O=C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzoic acid (0.050 g, 0.121 mmol), BOP (0.059 g, 0.133 mmol), DIPEA (0.07 mL, 0.363 mmol) and ethanolamine (0.011 g, 0.182 mmol) in DMF (0.5 mL) was stirred at rt for 12 hours. The crude product was purified by chromatography (silica, CH2Cl2: MeOH, 5:1) to afford the title compound as a brown oil (0.043 g, 78%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.64-7.59 (m, 3H), 7.54-7.46 (m, 4H), 7.41 (td, 1H, J=8.2 Hz, J=1.6 Hz), 7.35 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 7.15 (d, 2H, J=8.0 Hz), 5.42 (s, 2H), 5.24 (s, 1H), 3.91 (t, 2H, J=6.0 Hz), 3.24 (t, 2H, J=6.2 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H21F3N3O3: 456.4 (M+H), Found 456.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])=[CH:9][C:8]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 61.6 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (19 mg, 0.019 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (18 mg, 0.019 mmol) and cesium carbonate (454 mg, 1.4 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-(2,4,5-trifluoro-phenyl)-quinoline (compound of example 21) (400 mg, 0.93 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (97 mg, 1.11 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (250 mg, 62%). MS: m/z=437 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cnc(Cl)nc1N
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70° C. for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.O>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 162-1 and 4-trifluoromethoxyphenylboric acid (0.54 g) were dissolved in dioxane (10 mL) and 2 mol/L sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0.13 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]2[C:42]([F:43])=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][C:34]=2[F:44])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:33]2[C:42]([F:43])=[CH:41][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[F:44])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2c(F)cc(C(=O)O)cc2F)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A 60 ml portion of a methanol-THF (1:1) mixed solution of 2.09 g of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoate was mixed with 7.5 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred overnight at 80° C. The reaction solution was concentrated under a reduced pressure, 1 M hydrochloric acid was added to the thus obtained residue, and the precipitated solid was collected by filtration to obtain 2.02 g of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].O[C:13]1C=C(C=C(O)[CH:20]=1)CO>C(O)C.S(=O)(=O)(O)O>[CH2:13]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([OH:1])[CH:10]=[C:9]([OH:11])[CH:8]=1)[CH3:20]
Reactant: OCc1cc(O)cc(O)c1
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc(O)cc(O)c1

Procedure:
Synthesis of monomers was achieved from 3,5-dihydroxybenzoic acid or 3,5-dihydroxybenzyl alcohol as shown in above scheme. Commercially available 3,5-dihydroxybenzoic acid 1 was dissolved in ethanol along with catalytic amount of concentrated sulfuric acid and refluxed for 12 h to obtain ethyl-3,5-dihydroxybenzoate 1a. The ester 1a was then treated with one equivalent of alkyl halide to afford the mono alkylated ester 3 and 4. The yield of this reaction was rather low, because of the disubstituted byproduct obtained in the reaction along with the product as a statistical mixture. Compounds 3 and 4 were then reduced using LiAlH4 in dry THF under ambient temperature to give the monoalkylated phenols 3a and 4a. Compounds 2a and 5a were prepared by the reaction of 3,5-dihydroxybenzyl alcohol with 1 equivalent of alkyl halide under alkylation conditions. The phenols 2a-5a were then treated with tert-butylbromoacetate and sodium iodide to give compounds 2b-5b, which upon oxidation by PCC afforded the corresponding aldehydes 2c-5c. Treatment of aldehydes with methyl triphenylphosphonium bromide and potassium tert-butoxide under THF afforded the monomers 2d-5d. Polymers 2e-5e (n>1) was synthesized by nitroxide mediated living polymerization, using unimolecular intiator. The polymers were then hydrolyzed using potassium hydroxide as the base to afford carboxylic acid polymers 2f-5f.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:11]=1.[C:26](=O)([O:29]C)[O:27][CH3:28]>C1COCC1>[CH3:28][O:27][C:26](=[O:29])[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COC(=O)OC
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of LDA (2M in THF/heptane/ethyl benzene, 44 ml, 88 mmol) was added dropwise to a stirred solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyridine (10.5 g, 44 mmol) in dry THF (300 ml) under N2, such that the internal temperature remained <−70° C. After 1 hour at this temperature, dimethyl carbonate (8.9 ml, 106 mmol) was added. After 30 minutes the cooling bath was removed. When the internal temperature had reached −20° C. the reaction was transferred to a cold bath at −10° C., and then allowed to warm slowly to 0° C. After 1 hour at 0° C. the reaction was quenched with aqueous NH4Cl (half saturated, 100 ml). The reaction mixture was concentrated in vacuo. The residue was diluted with H2O (200 ml) and extracted with EtOAc (2×200 ml). The combined extracts were washed with brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10-30% EtOAc/isohexane to give the ester (9.2 g, 71%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ: 3.72 (2H, s), 3.75 (3H, s), 7.24 (1H, dd, J 1.4, 5.0), 7.72 (3H, t, J 8.4), 8.11 (2H, d, J 8.2), 8.68 (1H, d, J 5.0).
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7](C)[CH:6]=1>C(OCC)C>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: Cc1cc(Br)ccc1N
Solvent: CCOCC
Product: N#CNc1ccc(Br)cc1
Reaction time: 72 h
Yield: 91.8 %

Procedure:
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-methylaniline (Aldrich Chemical Company) (19.15 g, 103.4 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere. The reaction was filtered, and the filtrate was concentrated in vacuo at room temperature to give 4-bromophenylcyanamide (8.5 g, 92%) as an off white solid. HRMS: calcd for C8H7BrN2, 209.97926; found (EI, M+), 209.9788.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:16].[Li][CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([OH:16])[CH3:25]
Reactant: [Li]C
Reactant: Cc1ccc2c(C(=O)c3ccccn3)c(CCN(C)C)sc2c1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(C(C)(O)c3ccccn3)c(CCN(C)C)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−78° C.) solution of [2-(2-dimethylamino-ethyl)-6-methyl-benzo[b]thiophen-3-yl]-pyridin-2-yl-methanone (0.444 g, 1.50 mmol) in anhydrous toluene (5 mL), MeLi (1 mL, 1.6 mmol, 1.6 M in ether) was added and the mixture was stirred while the temperature was kept <−60° C. After 2 hours, an additional aliquot of MeLi (0.2 mL, 0.32 mmol) was added and stirring was continued for another 2 hours. The reaction was quenched with a mixture of 1.3 mL 6N HCl and 2.6 mL MeOH while keeping the temperature <−45° C. The mixture was allowed to warm to room temperature and the organic phase was separated. The organic phase was extracted with 500 mL of 1N HCl. The combined aqueous phases were neutralized with 50% sodium hydroxide and extracted 3 times with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (dichloromethane/MeOH=97/3 up to 85/15) afforded 1-[2-(2-dimethylamino-ethyl)-6-methyl-benzo[b]thiophen-3-yl]-1-pyridin-2-yl-ethanol in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:26][O:27][C:28]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=O)[CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:26][O:27][C:28]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:29]=2/[CH:30]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1cccc(F)c1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(OC(F)(F)F)cc2)c(/C=C/c2cccc(F)c2OCC2CC2)nc2sccn12
Yield: 44.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-cyclopropylmethoxy-3-fluorobenzaldehyde (291 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure outlined in Example 24 to give 241 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23 (d, J=4.8 Hz, 2H), 0.48 (d, J=6.6 Hz, 2H), 0.95-1.05 (m, 1H), 3.77 (d, J=6.9 Hz, 2H), 7.00-7.09 (m, 2H), 7.15-7.23 (m, 2H), 7.42-7.50 (m, 4H), 7.53 (d, J=4.8 Hz, 1H), 7.98-8.08 (m, 2H); ESI-MS (m/z) 503.55 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([CH3:30])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=2)=[C:23]([CH3:30])[CH:22]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1
Product: CSc1nc(Nc2ccccc2F)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-(4-fluoro-2-methyl-phenyl)-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.28 (s, 3H).59 (s, 3H), 7.01 (m, 2H), 7.18 (m, 3H), 7.24 (m, 1H), 8.42 (m, 1H), 9.63 (s, 1H), 11.30 (br s, 1H). LC MS (m/e)=372 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:21][C:15]=1[C:16](OCC)=[O:17].C(=O)(O)[O-].[Na+]>>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:14]3[N:13]=[C:2]4[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:7]4[C:16](=[O:17])[C:15]=3[CH:21]=2)=[O:34])=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1ccc(Cl)nn1
Reactant: CCOC(=O)c1cc(NC(=O)c2ccc(C)cc2)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc2nc3ccc(NC(=O)c4ccc(C)cc4)cc3c(=O)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 6-chloro-3-pyridazinecarboxylate (0.12 g, 0.64 mmol, Example 1, Step A) and ethyl 2-amino-5-[(4-methylbenzoyl)amino]benzoate (0.22 g, 0.74 mmol, Example 2, Step C) was heated as a melt at 165°-170° C. for 15 min. The resulting orange solid was suspended into saturated sodium bicarbonate solution, stirred at room temperature for 1 h then filtered. The solid was washed with water and diethyl ether to give ethyl 8-[(4-methyl-benzoyl)-amino]-10-oxo-10H-pyridazino[6,1-b]-quinazoline -2-carboxylate as an orange solid, mp 225°-230° C. dec.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[C:17]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=CC=CC=2)=C(S([O-])(=O)=O)C=C[C:21]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH:16]([C:17]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:35]=1)[CH2:21][CH2:22][NH:39][CH:36]([CH3:38])[CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Solvent: CC#N
Product: Cc1ccc(OCc2ccccc2)c(C(CCNC(C)C)c2ccccc2)c1
Temperature: 37.5 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (40 g), isopropylamine (20 ml), and acetonitrile (200 ml) was stirred at 35-40° C. for 12 hours. The reaction mass was distilled completely, and the obtained residue was crystallized from ethyl acetate (280 ml) to give 28 g of the title compound as a white crystalline powder. Melting point: 137-139° C.