Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11](C(OC)=O)[C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].C(=O)(O)[O-].[Na+]>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(CCc1cccc(C(F)(F)F)c1)C(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: O=C(O)CCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
The intermediate obtained in Step B (2.15 g, 7.07 mmol) was treated with 3.5 mL of a 4.53M solution of methanolic potassium hydroxide (15.9 mmol, 2.2 eq) and the resulting mixture stirred at room temperature for 72 hours. The mixture was concentrated under vacuum and the solid residue redissolved in 4 mL of concentrated hydrochloric acid and heated at reflux for 3 hours. The mixture was cooled, then extracted with methylene chloride (3×6 mL); the combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was suspended in 20 mL of water and treated with 700 mg (8.3 mmol) of sodium bicarbonate. The solution was washed with ether (2×20 mL); the aqueous phase was removed and acidified (pH 1-2) with 2N HCl. The mixture was extracted with methylene chloride and the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum. The residue was treated with 30 mL of concentrated hydrochloric acid and the mixture heated at reflux for 20 hours. All volatiles were removed under vacuum to afford 1.12 g (4.82 mmol, 68%) of product. 1H NMR (200 MHz, CDCl3): 1.98 (m,2H), 2.40 (t,8 Hz,2H), 2.74 (t,8 Hz,2H), 7.3-7.5 (m,4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=3)[CH2:13][CH2:12]2)=[O:10])[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Yield: 61.6 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (846 mg) described in Preparation Example 257 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Preparation Example 234, the title compound (579 mg) was obtained.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[O:40][CH3:41])=O>>[CH3:41][O:40][C:33]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: COc1ccc(OC)c(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c1

Procedure:
100 mg (0.152 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 49 mg (0.182 mmol) of 2-bromo-1-(2,5-dimethoxyphenyl)ethanone were reacted according to the General Method 3. Yield: 20 mg (24% of theory)
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11]([NH2:14])(=[O:12])=[O:13])=[CH:10][C:4]=1[SH:3]
Reactant: Nc1nc2ccc(S(N)(=O)=O)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(N)(=O)=O)cc1S
Yield: 126.2 %

Procedure:
A solution of 2-aminobenzothiazole-6-sulfonic acid amide (66 g, 287 mmol) and NaOH (90 g, 2.3 mol) in 400 mL of water was refluxed under argon overnight. The reaction solution was cooled in ice bath and was acidified to approximately pH 3 by the addition of concentrated HCl (˜180 mL). The resulting precipitate was isolated by filtration and dried to yield 74 g of 4-amino-3-mercaptobenzenesulfonamide as a white powder. MS (m/z, ES+): 205 (M+1, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:59])[CH3:58])[N:56]=4)[CH:40]=3)[CH2:35][NH:34]2)=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:58])[CH3:59])[N:56]=4)[CH:40]=3)[CH2:35][N:34]2[C:3](=[O:5])[C:2]([CH3:1])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1)C(=O)OCC
Reactant: C=CCCCCCC(C)(C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCCCCCC(C)(C)C(=O)N1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 2,2-dimethylnon-8-enoic acid (52, 239 mg, 1.3 mmol) in dry CH2Cl2 (10 mL) was added oxalyl chloride (165 mg, 2.6 mmol) and 2 drops of DMF. After 3 h at room temperature, the reaction mixture was concentrated and co-evaporated with toluene. This crude acid chloride was successively re-dissolved in CH2Cl2 and added to a stirred solution of 1-[[4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester (50, 380 mg, 0.65 mmol) and triethylamine (264 μL, 1.95 mmol) in CH2Cl2 (30 mL). After 1.5 h, the resulting solution was successively washed with a saturated solution of NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (gradient EtOAc/CH2Cl2 0:1 to 2:8) afforded the title product (53) as a colorless oil (490 mg, 100%): m/z=751 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]1[N:10]=[CH:9][CH:8]=[C:3]2[C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:4]2=[O:6]
Reactant: Nc1ccccc1B(O)O
Reactant: COC(=O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2c2cnccc12

Procedure:
Methyl 3-bromoisonicotinate (1.0 eq, 1.76 g, 7.65 mmol), 2-aminophenylboronic acid hydrochloride (1.0 eq, 1.33 g, 7.67 mmol) and cesium carbonate (2.0 eq, 4.99 g, 15.31 mmol) were suspended in dioxane (15 ml). The mixture was degassed by bubbling nitrogen for 10 minutes. PdCl2(dppf) (0.05 eq, 280 mg, 0.383 mmol) was added and the mixture was stirred at reflux for 2 hours. The resulting solid was filtered, washed with methanol, water and methanol and dried. Benzo[c][2,6]naphthyridin-5(6H)-one was isolated as an off-white solid (823 mg, 55% yield). LCMS (ES): 95% pure, m/z 197 [M+1]+.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH:5][C@H:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1Cl>[CH3:13][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:4][NH:5]1
Reactant: C[C@@H](NCCBr)c1ccccc1
Agent: Br
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1Cl
Product: C[C@H]1NCCc2ccccc21
Temperature: 145 °C
Reaction time: 0.67 h
Yield: 69.1 %

Procedure:
10.0 g(30.1 mmole) of (R)-(+)-N-(2-bromoethyl)-α-methylbenzylamine hydrobromide produced in Example 9(1) above was suspended in 60 ml of 1,2-dichlorobenzene and then heated to 145° C. 13.47 g(96.54 mmole) of anhydrous aluminum chloride (AlCl3) was added thereto over 40 minutes. The reaction solution was stirred for further 30 minutes at same temperature, cooled to room temperature and poured onto 250 g of ice-water with stirring. 30 ml of con. hydrochloric acid was added thereto and the mixture was stirred for 10 minutes. This solution was washed three times, each time with 130 ml of dichloromethane, and the resulting aqueous layer was separated, adjusted to pH 12 with sodium hydroxide and then extracted three times, each time with 250 ml of ethyl acetate. The extracts were combined, washed with 40 ml of saturated saline, dehydrated with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove ethyl acetate. The residue was distilled to obtain 3.06 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[O:34][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(-c2ccno2)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 5-(4-bromomethyl-phenyl)-isoxazole analogous to Example 1 to afford 4-chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-(4-isoxazol-5-yl-benzyl)-benzenesulfonamide: MS: m/e=496.0 (MH+), 513.2 (MNH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:26])=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C(N(CC)CC)C.S(Cl)(Cl)=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: NC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a mixture of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (430 mg, 1.00 mmol) and triethylamine (1.39 mL, 9.97 mmol) in N,N-dimethylformamide (5 mL) was added thionyl chloride (0.216 mL, 3.00 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. After the mixture was diluted with aqueous sodium bicarbonate, the resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow solid (317 mg, 0.773 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl[C:30]1C=CC(OC(C2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)C(OC)=O)=CC=1.CN(C)P(N(C)C)(N(C)C)=O.C(I)C>O1CCCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)([CH2:12][CH3:30])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCI
Product: CCC(Oc1ccc(Cl)cc1)(C(=O)OC)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.015 mole of lithium N,N-diisopropylamide (prepared as in example 55) in tetrahydrofuran is chilled to -65° C to -75° C. To the solution is added methyl (p-chlorophenoxy)[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of tetrahydrofuran. To the mixture is added 5 ml of hexamethylphosphoramide and while chilling to -65° C to -75° C, 4.68 g of ethyl iodide is added. After 1 hr., the mixture is allowed to warm to room temperature and stir overnight. The mixture is poured into water and extracted with ether. The ether extracts are washed with 10% hydrochloric acid, water, saturated NaHCo3, saturated NaCl solution and dried (MgSO4). Evaporation of the solvent gives the product as an oil.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)CCC>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.[Cu]I>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1csc([N+](=O)[O-])c1-c1ncco1
Yield: 17.7 %

Procedure:
The above titled compound (34 mg, 18%) was synthesized from 4-bromo-5-nitrothiophene-3-carbonitrile (203 mg, 0.87 mmol) and 2-tributylstannyloxazole (0.27 mL, 1.29 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089 mmol) and copper(I) iodide (16 mg, 0.084 mmol) according to methods described herein. LCMS method [4], retention time=1.62 min; MS(ESI) 222.0 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)=[O:4].C(O)(=O)C.C(OCC)(=O)C.[ClH:26]>C(O)C.[Fe]>[ClH:26].[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:15])=[CH2:1])=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: C=C(C)C(=O)Nc1ccc(N)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A mixture of 114 g of 2-methyl-N-(4-nitro phenyl) acrylamide (0.55 mol) and 92.6 g of Fe powder (1.65 mol=3 mol equiv.) was refluxed in 420 ml of ethanol. While refluxing, 400 ml of acetic acid (6.6 mol=12 mol equiv.) was added. A proper cooling and a safe gas separation were ensured. During the first reaction step a very strong exothermic gas release occurred. After completing of the addition of acetic acid, stirring while refluxing was continued for 60 min. After TLC inspection, 300 ml of ethyl acetate was added and the Fe salts were suction-filtered. The salts were then washed with 1.9 liter of ethyl acetate. While stirring, 138 ml of concentrated HCl (1.65 mol=3 equiv.) was added to the filtrate. The mixture was cooled to 5° C. while stirring. The precipitate was suction-filtered and washed with ethyl acetate. After drying at 40° C., 85 g of N-(4-amino phenyl)-2-methyl acrylamide hydrochloride was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20]COC)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CO>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C(N)=O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(CCO)ccc1OCc1ccccc1
Yield: 83.7 %

Procedure:
To a solution of 2-benzyloxy-5-(2-methoxymethoxyethyl)benzamide (721 mg) in methanol (10 ml) was added concentrated hydrochloric acid (0.7 ml), and the mixture was heated under reflux for 1 hour with stirring. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting insoluble material was collected by filtration to give 2-benzyloxy-5-(2-hydroxyethyl)benzamide (519 mg).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br>C(O)(=O)C.O>[C:4]1([CH:3]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][C:1]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: Sc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(Sc1ccccc1)c1ccccc1
Yield: 70.2 %

Procedure:
Cinnamic acid (30.0 g.), benzenethiol (24.0 g.) and 45% w/v hydrogen bromide in acetic acid (21.5 ml) were heated together at 100° for 7 hrs. The reaction mixture was diluted with water and steam distilled to remove unchanged thiol. The hot aqueous layer was decanted from the oily product, which was recrystallised from 60°-80° petrleum ether to give 3-phenyl-3-(phenylthio)propionic acid (36.7 g) m.pt. 85°-90°. A sample recrystallised again from 60°-80° petroleum ether had m.pt. 88°-90°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:30](=[O:37])[C:31]#[C:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2I)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:31](=[C:32](\[C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)/[C:33]([OH:36])([CH3:35])[CH3:34])/[C:30]2=[O:37])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)O)c2ccccc2I)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C#N)cc3)C(C)(C)O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.33 (s, 6H) 3.85 (s, 3H) 5.15 (s, 2H) 5.35 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.71 Hz, 1H) 7.03 (d, J=7.83 Hz, 1H) 7.15 (t, J=7.71 Hz, 1H) 7.48-7.55 (m, 1H) 7.52 (d, J=7.58 Hz, 3H) 7.62 (d, J=7.83 Hz, 1H) 7.89 (d, J=7.83 Hz, 1H) 7.99 (s, 1H) 8.05 (d, J=8.34 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1cc(-n2ccnc2)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 110° C. for 24 hours.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(C)C.O.O.[F-].[K+]>CN(C=O)C>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[CH:5]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 5-[(trimethylsilyl)ethynyl]-2-hydroxybenzoate (100 g, 0.57 mol) and potassium fluoride dihydrate (150 g, 1.59 mol) in DMF (600 ml) was stirred for 4 h at room temperature. The solution was extracted with ether (3×400 ml) and the combined ether extracts were washed with 1M HCl (2×200 ml) and water (2×100 ml). The ether layer was dried with Na2SO4 and evaporated to dryness. Yield 66.5 g (93% ).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43]([NH:45][CH3:46])=[O:44])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43]([NH:45][CH3:46])=[O:44])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CNC(=O)Cc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)Cc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 39.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}-N-methylacetamide (1.09 g) and pyridine hydrochloride (309 mg), the title compound (260 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH3:11])[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=C(S(O[Na])(=O)=O)C=CC=2OC)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]([CH3:11])[CH2:9][NH:8][C:4]1[CH:3]=[C:2]([C:30]2[CH:29]=[N:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:32][CH:31]=2)[N:7]=[CH:6][N:5]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccccc1C(C)CNc1cc(Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)O[Na])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)O
Product: COc1ccccc1C(C)CNc1cc(-c2ccc(N3CCN(C)CC3)nc2)ncn1
Temperature: 90 °C
Yield: 42 %

Procedure:
As shown in step 4-vi of Scheme 4, a mixture of 6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine (75.0 mg, 0.270 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (Compound 2007, 90.1 mg, 0.297 mmol), Pd(OAc)2 (1.21 mg, 0.00540 mmol), [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 11.1 mg, 0.0216 mmol), and Na2CO3 (405 μL of 2 M, 0.810 mmol) in IPA (2 mL) was degassed and back-filled with N2 (repeated 2×), then heated to 90° C. for 4 hours. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel (90-100% EtOAc in hexanes) to give N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine as a clear, yellow oil (Compound 2013, 48.0 mg, 42% yield): 1H NMR (CDCl3) δ 8.77 (d, J=2.2 Hz, 1H), 8.56 (s, 1H), 8.15 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.89 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 5.09 (bs, 1H), 3.87 (s, 3H), 3.76-3.65 (m, 4H), 3.65-3.46 (m, 3H), 2.62-2.48 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.7 Hz, 3H).