Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[Si](C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)c1cc2ccccc2o1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)c1cc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
Benzofuran-2-yl-trimethyl-silane (3.4 g, 17.86 mmol) was dissolved in methylene chloride (40 mL) and cool to −78° C. 4-Bromophenyl-acetyl chloride (19.65 mmol, 1.1 equiv.) was added at this temperature. Under vigorous stirring, a solution of TiCl4 (23 mL, 1M, 23.2 mmol, 1.3 equiv.) in CH2Cl2 was added dropwise and stirring continued for 20 min. Then the reaction was quenched with H2O (100 mL), cooling bath was removed and the mixture was allowed to warm up to room temperature. It was then diluted with H2O (100 mL) and extracted with CH2Cl2 (3×). Organic layers were combined, washed with brine, dried over MgSO4, solvent evaporated. Crude product thus obtained was subject to column purification. (silica gel, 10% EtOAC/Hexane). 980 mg of 1-Benzofuran-2-yl-2-(4-bromo-phenyl)-ethanone was obtained in 17% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cc(Cl)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(Cl)cc1C1OCCO1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzaldehyde (20.0 g, 0.128 mol), ethane-1,2-diol (40.0 g, 0.644 mol) and p-toluenesulfonic acid monohydrate (0.44 g, 2.56 mmol) dissolved in toluene (200 mL) was refluxed for 40 h with a dean-stark to remove water. After the reaction mixture was cooled to room temperature, EtOAc (200 mL) was added. Then the organic phase was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light-yellow solid (24.6 g).
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:36])[F:37])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH3:39])[CH2:12][CH2:11]1
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.040 mL, 0.50 mmol) was added to a suspension of 2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (0.035 g, 0.070 mmol) in MeOH (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.19 g, 0.10 mmol) was added in one portion and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). Solid NaHCO3 was added until the formation of gas ceased then the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 12 as a white solid (0.032 g, 89%); 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.44 (d J=2.2 Hz, 1H), 7.28-7.22 (m, 1H), 7.24-7.15 (m, 4H), 3.67 (s, 2H), 3.20-3.11 (m, 2H), 3.11-2.95 (m, 4H), 2.81-2.70 (m, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.28-2.13 (m, 2H), 1.87-1.70 (m, 4H). LCMS-A: rt 4.908 min; m/z 512.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6].[CH3:17][O:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.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>[CH3:17][O:18][C:19]1[C:24]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]#[N:6])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1ccc(Oc2ccccc2)c(Br)c1
Reactant: COc1ncccc1B(O)O
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: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1ccccc1
Temperature: 100 °C
Yield: 108.7 %

Procedure:
A mixture of 3-bromo-4-phenoxybenzonitrile (Preparation 21, 0.21 g, 0.7 mmol), (2-methoxypyridin-3-yl)boronic acid (0.2 g, 1.1 mmol) and sodium hydrogen carbonate (0.19 g, 2.1 mmol) was suspended in dioxane (10 mL) and water (3 mL). The reaction mixture was degassed for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.050 g, 0.07 mmol) was added and the mixture heated at 100° C. for 1 hour. After the reaction was allowed to cool to room temperature, the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The organic layer was filtered through a pad of celite and the solvent removed in vacuo to provide a crude brown solid. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in Heptane to afford the title compound as a yellow solid (0.23 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24](B(O)O)[CH:25]=1>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>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:25]=1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CCOC(=O)C(CC1CC1)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(CC1CC1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
250 mg (0.8 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) and 214 mg (0.96 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 35 mg (purity 87%, 9% of theory) of the title compound and 70 mg (22% of theory) of the product which is already hydrolysed (Example 6.1F)
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C([O-])(O)=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Na+].[Cl-]>O>[N:2]#[C:1][C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH2:9]
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)[C@@H](N)C#N
Temperature: 35 °C

Procedure:
A mixture of ethyl cyanoglyoxylate-2-oxime (50 g, 352 mmol) in 440 mL of water is cautiously treated with 340 mL of saturated aqueous NaHCO3, followed by portionwise addition of sodium hydrosulfite (165 g, 950 mmol). The reaction is then heated to an internal temperature of 35° C. for 35 min. After cooling to RT, the reaction is saturated with NaCl (approx. 250 g) and extracted with CH2Cl2 (6×150 mL). The combined CH2Cl2 extracts are dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 4.43 (1H, s), 4.34 (2H, q, J 7.2), 2.30 (2H, bs), 1.35 (3H, t, J 7.2).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1>>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([N:42]4[CH2:43][CH:40]([O:39][CH3:38])[CH2:41]4)=[O:23])[C:16]=3[N:15]=2)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: COC1CNC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: Cl
Product: COC1CN(C(=O)c2cccc3c2nc(C(=O)NC2CCN(C(C)C)CC2)n3Cc2cc(-c3ccc(Cl)s3)on2)C1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 205 mg (0.34 mmol) 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 46.6 mg (0.37 mmol) 3-methoxy-azetidine-hydrochloride. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid. Yield: 190 mg MS (ES+): m/e=597, chloro pattern.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(N2CCCCN2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.36 g, 13.6 mmol), the hydrochloride salt of the hexahydro-pyridazine (5.0 g, 41 mmol) and anhydrous potassium carbonate (11.3 g, 82 mmol) in N,N-dimethylacetamide (20 ml) was stirred at 115-120° C. under nitrogen for 3 days. A sample was analyzed by NMR showed complete conversion of the starting material. The resultant mixture was cooled to room temperature, poured onto cold water (200 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water and dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-(tetrahydro-pyridazin-1-yl)-phenylamine (1.9 g, 62.5%). The crude product was used in the next step without further purification.
Reaction SMILES: [I-:1].[Na+].Br[CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCI
Yield: 75 %

Procedure:
To a solution of 15 g (100 mmol) of sodium iodide in 120 ml of acetone was added 3 g (11 mmol) of N-(3-bromopropyl)phthalimide and the mixture was heated at reflux for 30 minutes. The cooled mixture was filtered and evaporated. The residue was partitioned between 50 ml of diethyl ether and 50 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 2.6 g (75%) of N-(3-iodopropyl)phthalimide as a white solid. [Mass spectrum (ESI) MH+ =316].
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:27])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([Cl:27])=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4-n-octyloxybiphenyl-4'-carboxylic acid (3.0 g) was heated under reflux together with an excessive amount of thionyl chloride for 6 hours, unaltered thionyl chloride was removed by distillation to give 4-n-octyloxybiphenyl-4'-carboxylic acid chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:22]3[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=3)[C:28]#[N:29])[CH2:19][C:18](=[O:30])[NH:17][C:9]=2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K86) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as an off-white solid (25 mg).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]1([CH:7]([NH:8][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: NC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 120 °C
Yield: 85.4 %

Procedure:
A mixture of crude (+/−)-1-cyclohexyl-1-{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanamine (405 mg, 1.21 mmol), methyl 6-fluoronicotinate (225 mg, 1.45 mmol), and potassium carbonate (501 mg, 3.62 mmol) in N,N-dimethylformamide (4.2 ml) was heated to 120° C. for 12 hours. The reaction mixture was diluted with water to precipitate a crude solid that was collected by filtration. The crude material was purified via ISCO MPLC (SiO2, 0-50% ethyl acetate in heptane) to yield the product (0.486 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 8.78 (s, 2H), 8.70 (d, J=1.6 Hz, 1H), 8.55 (d, J=8.2 Hz, 2H), 7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 6.31 (d, J=8.8 Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.84 (s, 3H), 1.97 (d, J=12.5 Hz, 1H), 1.59-1.88 (m, 5H), 1.04-1.34 (m, 5H). MS (M+1): 471.2.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(CO[C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[CH:26]=[O:27])=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][N:24]1[C:20]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(C=O)c1N1CCN(c2ccccc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
A mixture of 1-phenylpiperazine (3.40 g), 5-[(4-chlorobenzyl)oxy]-1-methyl-1H-pyrazol-4-carbaldehyde (600 mg), triethylamine (1.20 mL) and dimethylformamide (7.0 mL) was stirred at 120° C. for 8 hours, and then at a room temperature for 17 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and water was then added thereto. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 10:90), so as to obtain the title compound (669 mg) in the form of a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a suspension of 2,4,6-trichloro-1,3,5-triazine (5.0 g, 27 mmol, 1.0 equiv) in dichloromethane (50 ml) at −50° C., a premixed solution of ethyl 4-piperidinecarboxylate (4.1 ml, 27 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 14.2 ml, 81.3 mmol, 3.00 equiv) in dichloromethane (100 ml) was added dropwise via an addition funnel. The reaction mixture was allowed to warm to room temperature, and stirring was continued overnight. The solvent was removed under reduced pressure to yield 7.95 g (96%) of the title compound. MS (ES+): m/e 305.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24]O)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)cc1Cl
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=8.0 Hz), 2.76 (2H, t, J=8.0 Hz), 5.18 (2H, s), 5.74 (1H, d, J=0.8 Hz), 7.26 (2H, s), 7.40-7.44 (2H, m), 7.57 (1H, s), 8.03 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15ClN4O, 339. Found, 339.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O.CN(C=O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:2]2[C:10]3[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=3[NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)(=[O:13])=[O:14])[S:4][C:3]=2[C:23]2[CH:27]=[N:26][NH:25][CH:24]=2)[CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
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: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)cc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 110 °C
Yield: 48.6 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3,5-dimethoxyphenylboronic acid pinacol ester (90 mg, 0.343 mmol), potassium carbonate (95 mg, 0.685 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 μmol) were weighed into a microwave vial. 1,4-Dioxane (1.5 mL), DMF (0.75 mL) and water (0.38 mL) were added and the mixture heated in a microwave at 110° C. for 30 min. At this point, both reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (75 mL) and then with 2M NH3 in MeOH (100 mL). The basic methanolic solution was concentrated and purified by MDAP (acidic conditions), to give the title compound (45 mg). LCMS (A) m/z: 541 [M+1]+, Rt 1.26 min (acidic).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=O)[CH2:10][CH2:9][CH2:8]3.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]3[C:12](=[CH:13][C:2]1=2)[C:11](=[N:16][OH:17])[CH2:10][CH2:9][CH2:8]3
Reactant: O=C1CCCc2cc3c(cc21)OCC3
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2cc3c(cc21)OCC3

Procedure:
A mixture containing 46 g of the compound of Example 1, 60 g of hydroxylamine hydrochloride and 60 g of anhydrous sodium acetate in 410 ml of ethanol is brought to reflux for 5 hours. The mixture is then cooled and diluted with water, extracted with methylene chloride, dried and evaporated to dryness. The dry residue is recrystallized in ethanol.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)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].C(Cl)Cl.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:10]3[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1
Reactant: c1ccc(CCN2CCNCC2)nc1
Reactant: CCOC(=O)c1cc2cccc(Br)c2o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Temperature: 95 °C
Yield: 40 %

Procedure:
Ethyl 7-bromobenzofuran-2-carboxylate (0.900 g, 3.34 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (0.672 g, 3.51 mmol) were mixed in dry degassed dioxane (13 mL). To this mixture cesium carbonate (1.417 g, 4.35 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.159 g, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.153 g, 0.17 mmol) were added under argon and the reaction was heated at 95° C. over night. Water and DCM were added and the layers were separated. The aq phase was extracted with DCM (3×). The combined organic phases were washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by flash chromatography. (SiO2; DCM/MeOH 95/5) to give 0.507 g (40%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15].[C:16](Cl)(=[O:18])[CH3:17].O>ClCCl>[C:16]([O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH3:7])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)cc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
83 ml (1.02 mol) of pyridine are added to a solution of 120 ml (1 mol) of 2,4-dimethylphenol in 400 ml of dichloromethane cooled to 5° C. After stirring for 15 minutes and cooling the reaction mixture to -10° C., 73 ml (1.02 mol) of acetyl chloride in solution in 100 ml of dichloromethane are added dropwise. The reaction mixture is then brought to reflux for 2 hours, then cooled and treated by the addition of 200 ml of water, and then acidified to a pH of 1. The organic phase is extracted, dried over MgSO4 and filtered on a silica bed, to lead to the production of a yellow oil: 2,4-dimethylphenyl acetate: yield 98%.