Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Temperature: 90 °C
Yield: 73.2 %

Procedure:
2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol), K2CO3 (749 mg, 5.43 mmol) and [1,1′-Bis-(diphosphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2dppf) (74 mg, 0.091 mmol) were stirred in DMSO (2 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90° C. for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) provide the title compound (337 mg, 62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.06-8.02 (dd, J=8.3, 2.1 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.52-7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H), 3.52 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH2:8])=[CH:5][N:6]=1.CS[C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:11]([NH:12][N+:13]([O-:15])=[O:14])=[NH:16])=[CH:5][N:6]=1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Solvent: CCO
Product: N=C(NCc1cnc(Cl)s1)N[N+](=O)[O-]
Yield: 77.7 %

Procedure:
A mixture of 0.35 g of 2-chloro-5-thiazolemethanamine, 0.31 g of S-methyl-N-nitroisothiourea and 3 ml of ethanol was heated under reflux for 6 hours. After cooling, the separated crystals were collected by filtration, washed with a small amount of ethanol, and then recrystalized from ethanol to obtain 0.42 g of the title compound as crystals. This compound is No. 9 in Table 1. m.p.: 160.0°-162.0° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1cccc(F)c1
Reactant: C1CCNCC1
Product: N#Cc1cccc(N2CCCCC2)c1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:15])[CH2:14][O:13]1>CC#N.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]([CH3:15])([OH:13])[CH3:14])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CC1(C)CO1
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Br)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (5 g, 24.63 mmol), NaH2PO4 monohydrate (3.23 g, 23.40 mmol) and 2,2-dimethyloxirane (3.02 g, 41.9 mmol) in MeCN (90 ml) and H2O (10.00 ml) was stirred at 150° C. in a steel bomb for 4 hours. After cooling to RT, the mixture was diluted with a solution of saturated NaHCO3 (80 ml) and extracted with EtOAc (80 ml). The EtOAc extracts were dried over Na2SO4 and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc/hexane to elute 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (6.25 g, 22.72 mmol, 92% yield) as clear oil. LC MS at t=2.24 min. (m Na=297) PHENOMENEX® S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 6H), 3.79 (s, 2H), 3.84 (s, 3H), 6.77 (d, J=8.31 Hz, 2H), 7.01 (s, 1H), 7.26 (s, 1 H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C(#N)C>[OH:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:19]1[CH2:18][CH2:17][C:15]2([O:14][CH2:13][CH2:12][N:11]([C:9]([C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[O:10])[CH2:16]2)[CH2:21][CH2:20]1
Reactant: CC(C)c1csc(C(=O)N2CCOC3(CCNCC3)C2)n1
Reactant: OCCc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of (4-isopropylthiazol-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 66, step b) (0.28 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.171 g) in acetonitrile (20 mL) was treated with triethylamine (0.276 mL) and the reaction mixture stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent to afford the subtitled compound. Yield 0.25 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccnc1C=O
Reactant: CC(NCCCNC(=O)OC(C)(C)C)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCNC(=O)OC(C)(C)C)C(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of [3-(1-pyridin-2-yl-ethylamino)-propyl]-carbamic acid tert-butyl ester and 3-methyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave {3-[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-propyl}-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:22]>ClCCCl>[Cl:22][C:4]1[C:5]2[CH2:9][S:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CSC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Clc1ncnc2c1CSC2
Yield: 81.5 %

Procedure:
To a solution of the 5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (0.50 g, 3.2 mmol) in DCE (50 mL) was added DIEA (0.42 g, 3.2 mmol) and POCl3 (1.5 g, 9.8 mmol). The mix was refluxed overnight. After cooling, the solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (4:1) to give 4-chloro-5,7-dihydrothieno[3,4-d]pyrimidine (0.45 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.84 (s, 1H), 4.37 (s, 2H), 4.27 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:18])=[N:10][O:11][C:12]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O.C1(C)C=CC=CC=1>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9]([CH3:18])=[N:10][O:11][C:12]=3[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)Cc1onc(C)c1-c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CO/N=C(\COc1ccc(COc2ccc(-c3c(C)noc3CC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a 50 mL two neck RB flask fitted with magnetic stirrer was charged with 15 mL of toluene. To the stirred solvent were added methyl [4-(4-hydroxyphenyl)-3-methyl-1,2-oxazol-5-yl]acetate (0.3 g, 1.21 mmol), (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.33 g, 1.21 mmol) and tri-(n-butyl)phosphine (0.39 g, 1.94 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (0.49 g, 1.94 mmol) was added portion wise and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. The product was obtained as colorless oil (0.47 g, yield: 77%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.61 (m, 2H), 7.26-7.30 (m, 5H), 7.11-7.14 (d, 2H), 6.94-6.97 (d, 2H), 6.85-6.88 (d, 2H), 5.14 (s, 2H), 4.93 (s, 2H), 3.99 (s, 3H), 3.68 (s, 2H), 3.65 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Oc1ccc(CCc2ccc(Cl)cc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(4-chlorophenethyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (57%, white crystals). HPLC-MS: m/z=366.1 (M+1); Rt: 5.58 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][C:15]=12.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.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>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][C:15]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: OB(O)c1cc2ccccc2s1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cc4ccccc4s3)ccnc21
Temperature: 120 °C
Yield: 87.6 %

Procedure:
1-Benzothien-2-ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.10 g, 0.00031 mol) were combined in toluene (3.0 mL, 0.028 mol) and ethanol (1.0 mL, 0.017 mol). Potassium carbonate (0.085 g, 0.00062 mol) dissolved in water (1.0 mL) then was added and the reaction was degassed with nitrogen. Then tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.00004 mol) was added and the reaction was heated to 120° C. in a sealed tube in the microwave for 60 minutes. This was allowed to cool to rt, taken up in ethyl acetate and washed with water 2×, brine, dried over magnesium sulfate and concentrated to give 4-(1-benzothien-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine (0.10 gm) as an oil, LC/MS (M+H)+ 381.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N+:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[O-])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:21])C.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:21])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][N+](=Cc1ccc(Cl)cc1)CCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
4.0 G. of α-(p-chlorophenyl)-N-(2-morpholinoethyl)-nitrone are heated to 90° C. in 15 ml. of glacial acetic acid and 15 ml. of acetic anhydride for 24 hours. The mixture is then cooled to room temperature, poured into 200 ml. of ice-water and rendered basic with 20% sodium hydroxide solution. Thereafter, the mixture is extracted twice with 100 ml. of methylene chloride each time. The methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 0.13 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:19][CH2:18][C:17]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:19][CH2:18][C:17]4([CH2:28][C:27](=[O:29])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[O:20]4)[CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1CC2(CCNC2)Oc2ccccc21
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC(=O)c5ccccc5O4)C3)nn2)n1

Procedure:
The object product (148 mg, 62%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), spiro[chromene-2,3′-pyrrolidin]-4(3H)-one hydrochloride (160 mg) obtained in Example 21(2) and potassium carbonate (110 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>O>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:17]1[N:16]([CH2:15][CH2:14][CH2:13][O:18]1)[C:4]2=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C=NCCCCl
Solvent: O
Product: O=c1c2cccc(Cl)c2nc2n1CCCO2
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A 250 mL round bottom flask is charged with 2-amino-3-chlorobenzoic acid (5.00 g, 29.1 mmol) and 40 mL of 10% aqueous KHCO3. The slurry is cooled to 0° C., and 3-chloropropylisocyanate (5.25 mL, 51.2 mmol) is added. The reaction mixture is allowed to warm to room temperature over 3 h, warmed to reflux for 2 h, then stirred at room temperature for 16 h. It is then diluted with 40 mL H2O and cooled to 0° C. The product is collected by filtration to provide 5.68 g of a yellow solid. This material is purified by recrystallization: it is dissolved in a minimal volume of warm CH2Cl2 (ca. 10 mL), cooled to 0° C., and IPE (ca. 20 mL) added to the point of cloudiness; crystallization is allowed to proceed at that temperature for 1 h. The resulting yellow solid is collected and dried to provide 3.87 g (16.3 mmol, 56% yield) of light yellow solid.
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.[CH2:30]([OH:33])[CH:31]=[CH2:32].C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([CH2:32][CH2:31][CH:30]=[O:33])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C=CCO
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O=CCCc1ccc2ncccc2c1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Tris(dibenzylideneacetone)dipalladium (480 mg, 0.52 mmol) (Aldrich, Cat. #328774) and tri-tert-butyl-phosphonium tetrafluoroborate (300 mg, 1.0 mmol) in a flask was evacuated and refilled with nitrogen (2 times). 1,4-Dioxane (31 mL) was added followed by consecutive addition of 6-bromoquinoline (7.2 g, 35 mmol) (TCI, Cat. #B2015), 2-propen-1-ol (4.7 mL, 69 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (8.9 mL, 42 mmol). The reaction vessel was evacuated and refilled with nitrogen (2 times). The reaction mixture was stirred at 30° C. for 24 h. Diethyl ether (30 mL) was added to the reaction mixture and then filtered and washed with diethyl ether. The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (0-50%) to afford the desired product. (˜55%) LCMS (M+H)+: m/z=186.0; (M+H2O+H)+: m/z=204.0.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[NH:6][C:7]=1[CH3:8].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH3:8][C:7]1[NH:6][C:5]2[N:4]([C:3]=1[CH3:2])[C:23](=[O:26])[CH:24]=[CH:25][C:9]=2[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: COc1cccc(C(=O)Cc2nc(C)c(C)[nH]2)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cccc(C(=O)c2ccc(=O)n3c(C)c(C)[nH]c23)c1

Procedure:
The compound is prepared as described in example 20 with 55 mg (0.02 mmol) of 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(3-methoxyphenyl)ethanone hydrochloride (example LV), 250 mg (4.62 mmol) of sodium methylate and 74 mg (0.89 mmol) methyl propiolate.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][O:50][CH3:51])[CH2:44][CH2:43]3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][O:50][CH3:51])[CH2:44][CH2:43]3)[C:11]=12
Reactant: COCCN1CCN(c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 60 °C
Yield: 60 %

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (2 mg, 0.002767 mmol), and 2,2,2-trifluoroacetic acid (0.2132 ml, 2.767 mmol) was heated to 60° C. in a sealed vessel for 18 hours. After cooling to ambient temperature, the reaction was concentrated in vacuo, using toluene to azeotrope residual TFA. The resulting residue was dissolved in DCM, and purified by preparative TLC (0.5 mm thickness, Rf=0.50), eluting with 10% MeOH (containing 7N NH3) in DCM. The product was obtained as a pale yellow powder (1 mg, 48%). HPLC: 89% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm, m/z 603 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 11.87 (s, 1H), 9.81 (s, 1H), 8.44 (m, 1H), 8.26 (m, 2H), 7.98 (m, 1H), 7.63 (m, 2H), 7.42 (m, 1H), 7.28 (m, 3H), 6.22 (m, 1H), 3.75 (m, 1H), 3.61 (m, 3H), 3.39 (s, 3H), 2.73 (m, 4H), 1.5-2.2 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:22][C:23]1[C:40]([F:41])=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:49][C:50]([NH:52][C:53]1[C:54]([O:66][CH2:67][C:68]([F:71])([F:70])[F:69])=[N:55][C:56]([CH3:65])=[CH:57][C:58]=1[O:59][CH2:60][C:61]([F:64])([F:63])[F:62])=[O:51]>C(#N)C.O>[F:22][C:23]1[C:40]([F:41])=[CH:39][C:26]2[N:27]=[C:28]([S:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:49][C:50]([NH:52][C:53]4[C:54]([O:66][CH2:67][C:68]([F:71])([F:69])[F:70])=[N:55][C:56]([CH3:65])=[CH:57][C:58]=4[O:59][CH2:60][C:61]([F:63])([F:64])[F:62])=[O:51])[CH2:35][CH2:34]3)[NH:29][C:25]=2[CH:24]=1
Reactant: Fc1cc2nc(SCCN3CCNCC3)[nH]c2cc1F
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4cc(F)c(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
1-[2-(5,6-Difluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (4.00 g, 6.25 mmol) and potassium carbonate (31.26 mmol) were dissolved in acetonitrile (100 mL) and water (30 mL). While the solution was stirred under cooling with ice, 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (2.20 g, 5.22 mmol) was added thereto over 15 minutes. The temperature of the mixture was allowed to room temperature, and the mixture was stirred for 15 hours. Thereafter, the reaction mixture was diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (silica gel 150 g, hexane: acetone=4:1 to 2:1 to 1:1). The thus-obtained crystals were recrystallized from chloroform-hexane, to thereby yield 2-[4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (3.04 g, yield 91%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:28])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 2-ethoxy-1-(4-chloro-2-fluoro-5 -methoxyphenyl) -4-trifluoromethyl-6(1H)-pyrimidinone. m.p. 117°-119° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[NH:5][CH:6]=1.[NH2:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:13]([O:23][CH3:24])[CH:12]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClC(Cl)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:10][C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C:17]([OH:19])([CH3:20])[CH3:18])=[C:13]([O:23][CH3:24])[CH:12]=2)=[O:9])[NH:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c[nH]1
Reactant: COc1cc(N)ccc1OCC(C)(C)O
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1cc(NC(=O)c2cc(Br)c[nH]2)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-bromo-1H-pyrrole-2-carboxylic acid (1.00 g, 5.30 mmol), preparation described in step A of Example 2, and 1-(4-amino-2-methoxyphenoxy)-2-methylpropan-2-ol (1.12 g, 5.30 mmol), preparation described in step A of Example 4. in dichloroethane (46.0 mL) was added EDC (2.03 g, 10.6 mmol) and HOBT (1.62 g, 10.6 mmol) and the reaction was allowed to stir at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with sat.