Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O/[CH:4]=[C:5](/[C:11](=O)[C:12]([F:15])([F:14])[F:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[NH:18]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[NH2:19]>C(O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([N:18]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:19]2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)(F)F
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(C#N)cc2)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
A solution of (Z)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (2.41 g, 10.03 mmol) in ethanol (10 mL) was added dropwise to a stirred solution of 4-hydrazinylbenzonitrile hydrochloride (1.702 g, 10.03 mmol), in ethanol (50 mL) cooled to −10° C. The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was evaporated to dryness and the residue redissolved in EtOAc (100 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica (120 g) chromatography, elution gradient 10 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 1-(4-cyanophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.400 g, 77%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11]C(=O)OC(C)(C)C)[N:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
In 3 mL of dichloromethane, tert-butyl (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methylcarbamate (232 mg, 0.668 mmol, 1 equiv.) was dissolved and trifluoroacetic acid (0.496 mg, 0.331 mml, 6.5 equiv.) was added. The reaction mixture was stirred overnight at room temperature, extracted with aqueous sodium carbonate (c=1 mol/L), dried over magnesium sulfate and evaporated to give (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (127 mg) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].CN(C=O)C.C(N(CC)CC)C.[CH3:25][O:26][CH2:27][C:28]#[CH:29]>CCOC(C)=O.[Cu]I>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:29]#[C:28][CH2:27][O:26][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: C#CCOC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C(=O)OC)cc1F
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 61 %

Procedure:
To a mixture of methyl 4-bromo-3-fluoro-benzoate (2.5 g, 10.7 mmol) and copper (I) iodide (204 mg, 1.07 mmol) and palladium dichlorobis(triphenylphosphine) complex (753 mg, 1.07 mmol) under an atmosphere of argon was added DMF (21 mL) and the reaction mixture was cooled to 0° C. Triethylamine (1.95 mL, 13.9 mmol) was added followed by 3-methoxyprop-1-yne (997 μL, 11.8 mmol) and the reaction mixture was stirred at 60° C. for 70 minutes. The reaction mixture was cooled, diluted with EtOAc and filtered over Celite®. The filtrate was washed sequentially with 1 M HCl, 10% NH4OH and brine. The organic layer was separated, dried and concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using EtOAc-hexanes (10-100%) as eluent to give methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.45 g, 61%). ESI-MS m/z calc. 222.2. Found 223.2 (M+1)+; Retention time: 1.53 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=11.2, 8.8, 1.5 Hz, 2H), 7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[CH:11][CH:10]=2)O1.Cl[C:23]1[CH:24]=[CH:25][C:26]2[N:27]=[C:28]([NH:36]C(=O)C)[N:29]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[C:31]=2[N:32]=1>>[NH2:36][C:28]1[N:29]=[C:30]([CH:33]2[CH2:35][CH2:34]2)[C:31]2[N:32]=[C:23]([C:9]3[CH:10]=[CH:11][C:12]([N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])=[CH:13][CH:14]=3)[CH:24]=[CH:25][C:26]=2[N:27]=1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)cc2)OC1(C)C
Reactant: CC(=O)Nc1nc(C2CC2)c2nc(Cl)ccc2n1
Product: Nc1nc(C2CC2)c2nc(-c3ccc(N4CCCC4=O)cc3)ccc2n1

Procedure:
The experimental procedure of example 2 was repeated, except for the use of 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-pyrrolidin-2-one instead of 4-fluorophenylboronic acid and N-(6-chloro-4-cyclopropyl-pyrido[3,2-d]pyrimidin-2-yl)-acetamide instead of 6-chloro-4-propyl-pyrido[3,2-d]pyrimidin-2-ylamine. The resulting compound was characterized as follows: MS (m/z) 346.2 [M+H]+; HPLC Rt=2.67 minutes (Method B).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH:8]=[N:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([OH:13])[CH3:12].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH2:8][NH:9][C@H:10]([CH:14]([CH3:15])[CH3:16])[CH:11]([OH:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(C)[C@@H](N=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F)C(C)O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](NCc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F)C(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
Example 28A (399 mg, 1.477 mmol) and Example 107B (238 mg, 1.551 mmol) were dissolved in methanol (20 mL) and triethylamine (0.225 mL, 1.624 mmol). The orange solution was stirred at ambient temperature for 1 hour and 55 minutes, followed by the addition of sodium borohydride (123 mg, 3.25 mmol). After 4 hours, additional sodium borohydride (123 mg, 3.25 mmol) was added, and the reaction was stirred overnight at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to provide (3R)-3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methylene}amino)-4-methylpentan-2-ol (500 mg, 1.354 mmol) as an orange oil. The imine (500 mg, 1.354 mmol) in methanol (20 mL) was added to 5% palladium on carbon (100 mg) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 18 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated to a yellow oil, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-50% EtOAc in dichloromethane (30 mL/min) to provide the title compound (250 mg, 0.673 mmol, 49.7% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 372.0 (M+H); 1H NMR (300 MHz, MeOH-D4) δ 9.39 (d, J=1.8, 1H), 8.71-8.64 (m, 1H), 8.02 (dd, J=8.6, 3.6, 1H), 7.92 (d, J=8.3, 1H), 7.76-7.66 (m, 1H), 4.27-4.04 (m, 2H), 3.95-3.86 (m, 0.25H), 3.83-3.73 (m, 0.75H), 2.37 (t, J=5.6, 0.25H), 2.27 (dd, J=6.1, 4.6, 0.75H), 2.00-1.88 (m, 1H), 1.25-1.18 (m, 3H), 1.08-1.01 (m, 3H), 1.00-0.93 (m, 3H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH3:4][C:5]1([CH3:26])S[C@@H:8]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[C:11](=[O:12])[N:7]2[C@H:6]1[C:23]([OH:25])=[O:24].[CH3:27]O>C(O)(C)(C)C.[Pt]>[CH3:27][O:25][C:23]([C:6]([N:7]1[C:11](=[O:12])[C@@H:10]2[C@H:8]1[O:15][C:14]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:13]2)=[C:5]([CH3:26])[CH3:4])=[O:24]
Reactant: CO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Pt]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC(C)(C)O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Reaction time: 2.5 h
Yield: 87 %

Procedure:
Magnesium chloride (36 mg) was dissolved in a mixture of 2.5 ml of methanol and 0.5 ml of tertbutyl alcohol. To the solution was added 53 mg of methyl ester of penicillin G to prepare an electrolyte. With platinum electrodes (1 cm2) dipped into the electrolyte, electrolysis was continued for 150 minutes (about 6 F) at a temperature of less than 0° C. and 3 to 8 V by applying constant current of 10 mA. Thereafter, the reaction mixture was stirred for about 30 minutes and extracted with chloroform. The extract was treated in the same manner as in Example 1, giving 41 mg of contemplated compound in 87% yield. The results of instrumental analyses were found identical with those of Example 1.
Reaction SMILES: [C:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH2:21][Br:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c2ccccc2c2cc(CBr)ccc21
Yield: 80 %

Procedure:
To a stirred solution of N-Boc 3-Methylcarbazole (85 mg, 0.3 mmol) and N-bromo succinimide (54 mg, 0.3 mmol) in carbon tetrachloride (10 mL) was added benzoyl peroxide (10 mg), and the reaction was heated at reflux for about 12 h. The cooled reaction mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified using column chromatography on silica gel with hexane/ethyl acetate as eluant (86 mg, 80% yield). ES-MS (M-Br)+ 280.9 (calc. 280.15).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[CH3:40][O-].[Na+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][O:11][CH3:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 56 %

Procedure:
The solution of toluenesulfonate 90 (104 mg, 0.18 mmol) and NaOMe (25 wt. % in MeOH, 5 mL) in methanol (3.5 mL) was stirred at room temperature for 15 h. After reaction complete, the resulting solution was quenched with H2O. Reaction mixture was evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford the titled compound 91 (12 mg, 56%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][O:6][C:5]2([CH2:12][C@@H:11]([CH3:13])[C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:4][CH2:3]1.[CH3:18]/[C:19](/[C:23]#[CH:24])=[CH:20]/[CH2:21][OH:22].C([Li])CCC>C1COCC1>[OH:22][CH2:21][CH:20]=[C:19]([CH3:18])[C:23]#[C:24][C:10]1([OH:14])[CH:11]([CH3:13])[CH2:12][C:5]2([O:4][CH2:3][C:2]([CH3:1])([CH3:17])[CH2:7][O:6]2)[CH2:8][C:9]1([CH3:16])[CH3:15]
Reactant: C#C/C(C)=C\CO
Reactant: C[C@@H]1CC2(CC(C)(C)C1=O)OCC(C)(C)CO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C#CC1(O)C(C)CC2(CC1(C)C)OCC(C)(C)CO2)=CCO
Yield: 75.7 %

Procedure:
(-)-(10R)-3,3,8,8,10-Pentamethyl-1,5-dioxaspiro[5,5]undecan-9-one (1.31 g, 5.5 mmol) was reacted with Z-3-methylpent-2-en-4-yn-1-ol (0.65 g, 6.7 mmol) and n-butyllithium (1.6M in hexane, 8 mL, 12.8 mmol) in dry THF. The crude product obtained (yellow oil, 2.6 g) was purified by flash column chromatography (75% ether+25% hexane) followed by distillation using the Kugel-rohr apparatus (about 250° C., 0.06 mm Hg) to give the product as a colorless oil (1.40 g, 77%), [a]D +30.0° C. (c 1.05, CH3OH); ir and 1H nmr identical to those reported above for its antipode.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C(O)C>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ncnc(Cl)c1C
Solvent: CCO
Product: Cc1ncnc(Nc2ccc(Cl)cc2)c1C
Temperature: 130 °C
Yield: 59.9 %

Procedure:
To 4.3 g (0.03 mole) of 4-chloro-5,6-dimethylpyrimidine were added 3.8 g (0.03 mole) of p-chloroaniline and about 10 ml of ethanol; the mixture wasthen heated at 130° C. for about 3 minutes. The reaction mixture quickly became a solution and then the hydrochloride of the desired compound precipitated as the solution was allowed to cool. The crystals thus obtained were separated and ground to a powder and then made alkalineby the addition of a dilute aqueous solution of sodium hydroxide. The insolubles were collected by filtration, washed with water and dried. The resulting crystals were recrystallised from benzene, to give 4.2 g (yield 60%) of the desired Compound No. 25, in the form of colourless needles melting at 170°-173° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1.[OH-].[Na+]>>[F:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromopropoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Fluoro-N-(4-hydroxy-phenyl)-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26FNO6 [M+H]+: 468.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1.[CH:28]([O:41][C:42]([NH:44][C:45]1[NH:46][C:47](=[O:58])[C:48]2[N:49]=[CH:50][N:51]([CH2:54][C:55](O)=[O:56])[C:52]=2[N:53]=1)=[O:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:55](=[O:56])[CH2:54][N:51]4[CH:50]=[N:49][C:48]5[C:47](=[O:58])[NH:46][C:45]([NH:44][C:42]([O:41][CH:28]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[O:43])=[N:53][C:52]4=5)[CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OC(c3ccccc3)c3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2cc(Cl)ccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4cc(Cl)ccc4s3)C(=O)C2)c(=O)[nH]1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(5-chloro-benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzhydryloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.62 (brs, H), 11.25 (brs, 1H), 8.42-8.39 (m, 1H), 7.96 (s, 0.6H), 7.82 (s, 0.4), 7.78 (m, 1H), 7.46 (d, 4H), 7.39 (t, 4H), 7.31 (t, 2H), 6.87 (s, 1H), 5.17 (s, 1.2H), 5.06 (s, 0.8H), 4.53 (s, 0.8H), 4.29 (s, 1.2H), 4.25 (t, 1.2H), 4.08-4.06 (m, 2H), 3.87 (t, 0.8H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:14].[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[CH:31])([CH3:18])([CH3:17])[CH3:16].N1CCCCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20](=[O:32])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[C:30]#[C:31][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 70 °C

Procedure:
A mixture of 2-bromo-1-methyl-4-(propylsulfonyl)benzene (Intermediate 37; 14.86 g, 53.6 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 13.00 g; 48.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.37 g; 1.95 mmol) and piperidine (14.5 mL) was heated at 70° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with ammonium chloride and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The compound thus obtained as a brown sticky solid was recrystallized twice from EtOAc/petroleum ether to afford the title compound as a beige solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:47]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[Cl:40])(=[O:49])=[O:48])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C(O)c1ccc(NCCc2c(CCNS(=O)(=O)c3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 21 %

Procedure:
The intermediate from Example 143 step 12 was treated with 2-chloro-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 21% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:20]=2[N:19]=[C:18]1[CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:20]=3[N:19]=[C:18]2[CH2:35][CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCSc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 104.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 4-chlorobenzenethiol (868 mg, 6.00 mmol) in DMF (5 mL) was added to a mixture of sodium hydride (60% dispersion, 240 mg, 6.00 mmol) in DMF (15 mL); the reaction became homogeneous and was stirred for 15 minutes. Solid 1-(5-chloropentyl)-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (1.93 g, 5.00 mmol) was added in small amounts, and the reaction was stirred for 1.5 hours. Water (25 mL) was added, and the resulting solution was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (5×30 mL) and brine (2×10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a colorless oil, which crystallized overnight. The solid was dried for three hours under high vacuum to provide 2.58 g of 1-[5-(4-chlorophenylsulfanyl)pentyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3nc4ccccc4[nH]3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 2-mercapto-benzimidazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:18]([N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1)[CH3:19]>C1COCC1.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]>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:24]1[N:20]([CH2:18][CH3:19])[N:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCn1nccc1-c1cc(C(=O)OC)sc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (300 mg, 1.17 mmol) in THF (2 mL) was added Na2CO3 (2M, 1.76 mL, 3.52 mmol), Pd(dppf)Cl2 (86, 0.117 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.41 mmol). The reaction mixture was heated to 80° C. in a sealed tube under N2. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 20-50%) to afford the title compound (0.272 g, 82%) as a light yellow syrup: LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:22])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[N:23]1([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[N:23]1([C:27]2[C:32]([CH:33]([C:7]3[CH:8]=[N:9][N:10]([CH3:22])[C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)[OH:34])=[C:31]([Cl:35])[N:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1c(Cl)ncnc1N1CCC1
Reactant: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 74 μL, 0.185 mmol) was slowly added drop-wise to a −78° C. solution of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C14) (50 mg, 0.14 mmol) in tetrahydrofuran (2 mL). The reaction mixture was allowed to stir at −78° C. for 1 hour, and then a solution of 4-(azetidin-1-yl)-6-chloropyrimidine-5-carbaldehyde (C12) (28.1 mg, 0.142 mmol) in tetrahydrofuran (1 mL) was added. Stirring was continued for 1.5 hours at −78° C., then water was added, and the reaction mixture was removed from the cooling bath. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Eluent: 94:5:1 dichloromethane/methanol/triethylamine) provided the product. Yield: 40 mg, 0.094 mmol, 67%. LCMS m/z 425.2, 427.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.17-2.26 (m, 2H), 3.72 (s, 3H), 3.89-3.97 (m, 2H), 4.23-4.31 (m, 2H), 6.32 (s, 1H), 7.58 (s, 1H), 7.79 (br d, J=8 Hz, 1H), 7.85 (s, 1H), 7.92 (br dd, J=8, 2 Hz, 1H), 8.58 (br d, J=2 Hz, 1H).