Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[C:6]=1[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1cc(C)cc(OC)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a suspension of 1,3-dimethoxy-5-methyl-benzene (5.10 g, 33.55 mmol) and succinic anhydride (3.69 g, 36.91 mmol) in nitrobenzene (100 mL) was added AlCl3 (8.9 g, 67.10 mmol). The reaction mixture was stirred at room temperature for 16 hours then carefully poured into aqueous NaOH. The pH was adjusted to 10 with solid NaOH and the aqueous solution washed with dichloromethane. The pH of the aqueous solution was adjusted to 3 with concentrated HCl and extracted with EtOAc. The organic extracts were dried and concentrated in vacuo. The residue was triturated dichloromethane to give 4-(2,4-dimethoxy-6-methyl-phenyl)-4-oxo-butyric acid as a pale yellow solid (3.7 g, 43%). 1H NMR (400 MHz, MeOD-d4) δ 6.44 (s, 1H), 6.40 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.03 (t, J=8.1 Hz, 2H), 2.60 (t, J=8.1 Hz, 2H), 2.19 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][PH:9](=[O:12])[O:10]C)(=[O:3])[CH3:2].[I-].[Na+:14]>CC(CC)=O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][PH:9](=[O:10])[O-:12])(=[O:3])[CH3:2].[Na+:14]
Reactant: CO[PH](=O)CCCCCC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)CCCCC[PH](=O)[O-]

Procedure:
A solution of methyl acetylpentylphosphinate (5.0 g, 0.026 mol) and oven-dried sodium iodide (3.9 g, 0.026 mol) in freshly distilled ethyl methyl ketone (50 ml) was refluxed for 1hour.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[N:18]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[C:17](=[O:27])[C:16]2=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]2[N:14]=1)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:33][C:34]1[N:35]=[CH:36][N:37]=[C:38]([NH:1][C@H:2]([C:13]2[N:18]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:17](=[O:27])[C:16]3=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][N:15]3[N:14]=2)[CH2:3][CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:39]=1[C:40]#[N:41]
Reactant: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)ncnc1N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
In a reactor vessel (S)-2-(1-amino-3-(benzyloxy)propyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (42 mg, 0.1 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (16 mg, 0.1 mmol) were dissolved in 1-butanol (840 μl) under argon atmosphere. N,N-Diisopropylethylamine (76 μl, 0.87 mmol) was added and the reaction mixture was heated at 120° C. overnight. Further N,N-diisopropylethylamine (76 μl, 0.87 mmol) was added afterwards and the reaction mixture was stirred at 120° C. overnight. The crude was evaporated and purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to obtain 34 mg (64% yield) of the title compound as a yellow solid. Purity 97%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[O:9][C:12](=[O:13])[N:11]([CH3:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1nncc(Cl)c1Cl
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1nncc(Cl)c1Cl)c1ccccc1
Yield: 13.4 %

Procedure:
A solution of 4,5-dichloro-3-hydroxypyridazine (0.49 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (20:80)) yielding the title compound (0.12 g, 14% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[CH:2].Cl[C:16]([O:18][CH3:19])=[O:17].[H-].[Na+].Cl>O1CCCC1>[CH3:19][O:18][C:16]([NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[CH:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)=[O:17]
Reactant: COC(=O)Cl
Reactant: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)NC(=O)OC)cc1[N+](=O)[O-]
Temperature: -10 °C
Yield: 40.8 %

Procedure:
3 g (0.016 mol) 4-Ethynyl-3-nitrobenzamide (Compound I-1), 45 ml tetrahydrofuran and 6 ml methyl chloroformate were added into a 100 ml four-neck reactor flask, stirred to dissolve and cooled to −10° C., and 7.5 g sodium hydride was added and maintained at about 0° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into crushed ice and the pH was adjusted to acidic with hydrochloric acid, and then extracted with 200 ml ethyl acetate. The organic layer was washed with water for three times, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain about 3.5 g crude product, which was separated by column chromatography to obtain N-methoxycarbonyl-4-ethynyl-3-nitrobenzoateamide (Compound I-2), 1.6 g (0.0065 mol), yield 40.8%.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:64])[C:9]1[S:10][C:11]([S:62][CH3:63])=[C:12]([S:14]([C:17]2[CH:18]=[C:19]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[N:39]=[N:40][N:41](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:42]=3)=[O:32])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].C(Cl)Cl>>[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[CH3:63][S:62][C:11]1[S:10][C:9]([C:8]([NH2:64])=[NH:7])=[CH:13][C:12]=1[S:14]([C:17]1[CH:18]=[C:19]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]2[N:39]=[N:40][NH:41][N:42]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCc2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCc2nn[nH]n2)c1
Yield: 45 %

Procedure:
A solution of {imino-[5-methylsulfanyl-4-(6′-methyl-2′-{3-[4-(2-trityl-2H-tetrazol-5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (15 mg, 16 μmol) in TFA/DCM (1:1, 2.0 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (3 to 7.5% containing 0.1% TFA) to give the title compound (5 mg, 45% yield) as a white solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(O[C:8](=[O:16])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])C.C(O)(=O)C.O>C(OCC)C>[CH2:14]([N:11]([CH2:12][CH3:13])[C:9](=[O:10])[C:8](=[O:16])[CH2:1][CH3:2])[CH3:15]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C(=O)N(CC)CC
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(=O)C(=O)N(CC)CC
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 68.1 %

Procedure:
mL ethyl magnesium bromide solution (191.8 mmol, 1.10 eq) were diluted with 182.6 mL diethylether. The solution was cooled to −15° C. and a solution of 30.20 g of compound (8) as obtained from example 1 (174.4 mmol) in 60.4 mL diethylether was added dropwise. The resulting viscous suspension was stirred for additional 75 min at −15° C. Subsequently, the reaction was quenched by addition of 14.96 mL acetic acid (261.6 mmol, 1.5 eq). Then, 35 mL water were added to dissolve all salts and the cooling bath was removed. After 15 min, the mixture was washed twice with 200 mL, pH-7-buffer and the organic phase was dried over 20 g sodium sulfate and was filtered. The filter cake was washed with 40 mL diethylether. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the crude product (26.33 g, 96% by weight) was obtained as a yellow liquid. Purification was achieved using a high vacuum distillation (bp 86° C. at 2.5 mbar) furnishing the title compound (18.66 g, 118.7 mmol, 68% by weight) as colorless liquid.
Reaction SMILES: C=O.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CO.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:36][N:6]1[CH2:7][CH2:8][N:3]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH2:4][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)cc4)CC3)C2)c2ccccc21
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
Formaldehyde (10.0 mg, 0.000333 mol) was added to a solution of (1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl}carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (0.13 g, 0.00032 mol, example 421, step 1) in methanol (1.0 mL, 0.025 mol) followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol), and the mixture was stirred for 1 h. The crude product was purified by prep-HPLC. LC-MS: 432.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([OH:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([O:18][CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2c(Cl)cc(Cl)c(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2c(Cl)cc(Cl)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To 120 mg of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent in vacuo gave 125 mg (99% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CO>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(Br)c2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 39.5 %

Procedure:
A mixture of iron (Aldrich 99.99+%, 13.85 g, 248.0 mmol) and crude 7-bromo-5-nitro-1H-indazole (20.00 g, 82.63 mmol) in glacial acetic acid (100 mL) was heated at about 80° C. in a 2-neck round bottom flask equipped with a mechanical stirrer and a nitrogen line with a bubbler. After about 2.5 hours, MeOH (100 mL) was added, warmed, and filtered hot through Celite®. The Celite® pad was washed with additional MeOH (4×100 mL) and the combined organic layers were concentrated under reduced pressure. The residues were basified to pH ˜7 using aqueous Na2CO3 (2M) and the product was extracted into EtOAc (1 L) over about 16 hours. The layers were separated and the aqueous layer was further extracted with additional EtOAc (3×500 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, decanted, and concentrated. The resulting solid was pre-adsorbed onto silica and purified by silica gel chromatography using heptane/EtOAc (1:1) as the eluent to afford 7-bromo-1H-indazol-5-ylamine (6.92 g, 40%); 1H NMR (DMSO-d6, 400 MHz) 12.92 (br s, 1H), 7.87 (s, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.77 (d, J=1.2 Hz, 1H) 4.96 (br s, 2H); LC-MS (Table 1, Method e) Rt 0.83.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][N:43]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:42][CH2:41]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(C(F)(F)F)c3)noc2C)CC1
Yield: 64.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (524 mg, 1.18 mmol, 64%) was obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:27][CH2:26]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:35](=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][N:28]2[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:30][CH2:29]2)[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (129 mg, 0.796 mmol) was added to a solution of 5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoic acid (111) (219 mg, 0.613 mmol) in anhydrous dichloromethane (8 mL) and the mixture was stirred at room temperature for 2 hours. N-Boc piperazine (148 mg, 0.796 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for an additional 16 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by Biotage silica gel column chromatography using methanol/dichloromethane (gradient 0% to 2%) to give 4-{5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoyl}piperazine-1-carboxylic acid tert-butyl ester 112 as a viscous, yellow oil (309 mg, 96%): 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.48 (s, 9H), 1.55 (m, 6H), 1.66 (m, 2H), 2.35 (m, 8H), 2.48 (m, 6H), 3.11 (m, 2H), 3.40 (m, 2H), 3.44 (m, 4H), 3.58 (m, 2H), 5.30 (br, 1H). m/z (ESI) 526 [C27H51N5O5+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCN(CC)CC.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.[Cu]I>[CH3:17][C:14]1[N:13]=[C:12]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:16][CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C#C[Si](C)(C)C)cc2)c(C)c1

Procedure:
[3-(4-Bromobenzenesulfonyl)-6-methylpyridin-2-yl]-(2,4,6-trimethylphenyl)-amine, prepared as described in Example 46, (100 mg, 0.225 mmol), Pd(PPh3)2Cl2 (7.9 mg, 0.011 mmol), CuI (2.1 mg, 0.011 mmol) and trimethylsilylacetylene (0.038 mL, 0.270 mmol) were heated at 50° C. in Et3N (0.5 mL) for 16 h. The reaction mixture was stripped in vacuo and the residue was chromatographed on silica gel using 10% EtOAc/hexanes as eluent to give 53 mg [6-methyl-3-(4-trimethylsilanylethynyl-benzenesulfonyl)-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine.
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:10]3[CH:9]=[C:8]([OH:7])[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[N:11]=3)[CH:20]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)c1cccc(-c2cccc(-c3cc(OC(=O)OC(C)(C)C)n(-c4ccccn4)n3)c2)c1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: CN(C)c1cccc(-c2cccc(-c3cc(O)n(-c4ccccn4)n3)c2)c1
Yield: 99 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 42 of Example C-16 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([O-:23])=[CH:21][CH:20]=1.[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([O:23][C:4]2[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7](=[CH:12][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: Cc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(C)cc2)cc1C(=O)OC

Procedure:
Dimethyl 4-nitrophthalate was reacted in DMF with sodium 4-methylphenoxide to give dimethyl 4-(4-methylphenoxy)phthalate in analogy to a process known from the literature (J. Org. Chem. Vol. 42, No. 21, 1977, 3419-3425). After standard working up and chromatography using hexane/EA, the diester was isolated as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Cl)c3)c2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (0.500 g, 1.54 mmol) and potassium carbonate (0.213 g, 1.54 mmol) was added dimethylformamide (5 mL). To this under N2 was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.482 g, 1.54 mmol) as a solution in dimethylformamide (2 mL). This was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-50% ethyl acetate in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.72 (d, J=4.5 Hz, 1H), 8.26-8.22 (m, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.43 (dd, J=8.0 Hz, J=4.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.05-7.02 (m, 2H), 6.70 (d, J=7.2 Hz, 1H), 5.60 (s, 2H), 1.62 (s, 9H). HRMS (M+1)=555.0826.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:11]=2[C:12]#[N:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>COCCOCCOC.Cl.O>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([S:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:11]=1[C:12]#[N:13]
Reactant: Cc1cc(C)cc(Sc2cccc([N+](=O)[O-])c2C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(C)cc(Sc2cccc(N)c2C#N)c1
Yield: 64 %

Procedure:
2-[(3,5-Dimethylphenyl)thio]-6-nitrobenzonitrile (Example 5) (1.0 g, 0.0035 mol) was dissolved in 50 ml of diglyme. A solution of stannous chloride-2H2O (3.16 g, 0.014 mol) in 15 ml of concentrated HCl was added dropwise with stirring. After stirring 1 h and 15 min, the reaction mixture was poured into a solution of 12 g NaOH in 100 ml of water with ice added to bring the total volume to 300 ml. The mixture was stirred for 1 h and the solid was collected by vacuum filtration. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.57 g (64%) of 2-amino-6-[(3,5-dimethylphenyl)thio]benzonitrile: mp 124°-125° C.; NMR (Me2SO-d6, 300 MHz) δ 2.23 (s, H), 6.17 (br, 2H), 6.24 (apparent d, 1H), 7.00 (m, 3H), 7.09 (apparent t, 1H); mass spec (CI) 255 (M+ +1, 100%). Anal. Calc. for C15H14N2S: C, 70.83; H, 5.55; N, 11.01; S, 12.61. Found: C, 70.84; H, 5.60; N, 10.98; S, 12.53.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:15]=[C:16]1CC[CH2:18][CH2:17]1>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C(OC(C)C)=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:3]1(=[CH:2][CH2:1][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C=C1CCCC1
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC=C2CCCC2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of methyl 4-(allyloxy)benzoate 26.1 (3.00 g, 16.0 mmol) and methylenecyclopentane (1.9 g, 23.0 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) in DCM (5.0 mL) was added Hoveyda-Grubbs reagent (0.39 g, 0.62 mmol), (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) at room temperature. The resulting reaction mixture was degassed three times and then stirred at 55° C. under nitrogen overnight. The reaction mixture was purified by CombiFlash® silica gel column chromatography (hexane/EtOAc 95/5) to give 26.2, (2.60 g, yield 68%). 1H NMR (500 MHz, CDCl3) δ ppm 7.82-7.93 (2H, m), 6.80-6.88 (2H, m), 5.44-5.56 (1H, m), 4.47 (2H, d, J=6.6 Hz), 3.80 (3H, s), 2.20-2.31 (4H, m), 1.50-1.71 (4H, m).