Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(OCC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].[OH-].[Na+]>O.C(OCC)(=O)C>[C:16]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 13.8 g. (0.10 mol) of m-nitroaniline in 100 ml. of diethyl ether and 30 ml. of ethyl acetate was added 9.0 g. (0.10 mol) of acryloyl chloride and a solution of 4.0 g. (0.10 mol) of sodium hydroxide in 20 ml. of water. The mixture was stirred overnight (18 hours) at ambient temperature and the precipitate filtered to give N-propenoyl-3-nitroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)[N:12]=[C:11]2[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3c(OC)cccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [5-methoxy-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of [4-(2-nitro-phenylamino)-phenyl]-acetic acid methyl ester (0.700 g, 2.45 mmol) and Pd/C (10%) (0.240 g) in MeOH (20 mL) is stirred for 3 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated to afford the title compound as a black oil: ES-MS: 257.1 [M+H]+; single peak at tR=3.04 min (System 1).
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[S:10][CH:11]=[C:12]([CH3:14])[CH:13]=1)(=[O:8])C>>[CH3:14][C:12]1[CH:13]=[C:9]([C:6]([OH:8])=[O:2])[S:10][CH:11]=1
Reactant: [O-]Cl
Reactant: CC(=O)c1cc(C)cs1
Agent: [Na+]
Agent: [OH-]
Product: Cc1csc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To an aqueous solution of sodium hypochlorite (available chlorine 5%) (92.6 mL, 143.0 mmol) at about 0° C. was added sodium hydroxide (1.14 g, 28.6 mmol) and the mixture was stirred at about 0° C. until all of the sodium hydroxide had dissolved. To this solution was added 2-acetyl-4-methylthiophene (2.0 g, 14.3 mmol) at about 0° C. After the addition was complete, the mixture was heated to about 70° C. for about 3 hours, then the solution was cooled and was carefully quenched by addition of a solution of sodium bisulfite (23 g) in water (150 mL). After stirring for about 20 minutes, the solution was acidified by addition of concentrated hydrochloric acid and the precipitate was collected by filtration and dried under high vacuum to provide the desired product. MS (DCI-NH3): m/z 160 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.043 mmol) in Acetonitrile (0.5 mL) was treated with 4-fluorobenzyl chloride (0.025 mL, 0.213 mmol) and Cs2CO3 (69 mg, 0.213 mmol) and then stirred at 70° C. for 2 hours. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(4-fluorobenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate as pale a yellow solid which was used with no further purification. LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([CH:24]([Cl:28])[C:25]([NH2:27])=[O:26])CCC.[C:29]1([CH3:35])[CH:34]=[CH:33]C=CC=1>>[Cl-:28].[CH2:33]([NH:27][C:25]([CH2:24][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:26])[CH2:34][CH2:29][CH3:35]
Reactant: Cc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC(Cl)C(N)=O
Product: CCCCNC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.1 %

Procedure:
A solution of triphenyl phosphine (26.23 g, 0.1 mol) and n-butyl chloroacetamide (14.96 g, 0.1 mol) in toluene (250 mL) was refluxed with stirring for 22 h. After cooling to room temperature, the mixture was filtered and dried under high vacuum to afford 36.72 g (89.1% yield) of the title compound as white crystals. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[C:10]1([CH3:23])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.FC(F)(F)C1C=CC=C[C:28]=1[O:29]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:28]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH3:23])[CH2:18][CH2:19]2)=[O:29])=[CH:7][CH:6]=[N:5]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Cc1ccccc1OC1CCNCC1
Reactant: Cn1nccc(N)c1=O
Agent: Cl
Product: Cc1ccccc1OC1CCN(C(=O)Nc2ccnn(C)c2=O)CC1
Yield: 50 %

Procedure:
Compound 59 is prepared from intermediate 4c and from 4-o-tolyloxy-piperidine (obtained following the method described for intermediate 1a), applying synthesis method 7 (yield: 50%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[NH:30][CH2:29][CH2:28][O:27][CH3:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with 2-methoxy-ethylamine gives “A92”; method 1: HPLC/MS: 1.25 min, [M+H]=392;
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C[Si](OC(=O)C)(OC(=O)C)OC(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Agent: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 96 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0032 mg of methyltriacetoxysilane was added. Next, 0.0045 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.04 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 98% and phenethyltriethoxysilane was produced at a yield of 96%. The yield of (α-methylbenzyl) triethoxysilane was 0.7%.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:45][NH:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50].CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([N:46]([CH3:45])[CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CNCCS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](C(=O)N(C)CCS(C)(=O)=O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). N-methyl-2-(methylsulfonyl)ethanamine (10.60 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (12 mg, 57% yield). 1H NMR (500 MHz, CD3OD) δ 0.77 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.49 (m, 1H), 2.97 (s, 3H), 3.05 (s, 3H), 3.36 (t, J=6.5 Hz, 2H), 3.78 (t, J=6.5 Hz, 2H), 4.81-4.96 (m, 2H), 5.36 (d, J=11.0 Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 12.39 (s, 1H). [M+H] calc'd for C18H23FN4O4S, 411; found, 411.
Reaction SMILES: N[C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1C=O.[C:17]([CH2:19][C:20](Cl)=O)#[N:18].C[N:24]([CH3:27])C=O>>[CH2:15]([C:12]1[CH:11]=[C:5]2[C:4]([O:3][C:2]3[CH:20]=[C:19]([C:27]#[N:24])[CH:17]=[N:18][C:7]=3[C:6]2=[O:10])=[CH:14][CH:13]=1)[CH3:16]
Reactant: CCc1ccc2oc(N)c(C=O)c(=O)c2c1
Reactant: N#CCC(=O)Cl
Reactant: CN(C)C=O
Product: CCc1ccc2oc3cc(C#N)cnc3c(=O)c2c1

Procedure:
In 40 ml of dimethylformamide was dissolved 1.82 g of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde, followed by the addition of 3.5 g of cyanoacetyl chloride. The mixture was reacted at 60° C. for 3 hours, with constant stirring. The solvent was then distilled off under reduced pressure and the residue was chromatographed on silica gel. The desired product was recovered from the chloroform eluate and recrystallized from acetonitrile. By the above procedure was obtained 1.03 g of 7-ethyl-3-cyano-1-azaxanthone, m.p. 183°-185° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:20])[CH3:19])[CH:2]=1.[CH:21](OC)(OC)[O:22]C.[CH3:28]O>[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:28][O:20][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([O:22][CH3:21])[CH3:19]
Reactant: CC(=O)c1ccccc1Oc1cnc2ccccc2c1
Reactant: CO
Reactant: COC(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: COC(C)(OC)c1ccccc1Oc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
After 0.13 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone and 0.06 g of trimethyl orthoformate were dissolved in 1.5 ml of methanol, 0.02 g of tetrabutylammonium tribromide was added and the mixture was stirred for 4 days at room temperature. The reaction mixture was concentrated and then purified by silica gel column chromatography to obtain 0.08 g of 3-[2-(1,1-dimethoxy-ethyl)-phenoxy]-quinoline (Compound Number 27).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O.O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.S([O-])([O-])(=O)=O.[Ca+2]>C(O)C.[Pd].CC(O)=O>[N:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH:1]/[C:16](/[CH3:18])=[CH:15]\[C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:6]=2[NH:10][CH:9]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(/C)Nc1ccc2nc[nH]c2c1

Procedure:
An 82 g. (0.5 mole) sample of 5-nitrobenzimidazole in 900 ml of ethanol was reduced over 4 g. of 5% Pd/C catalyst containing 50% H2O. After a pressure drop of 108 lb. (calcd. 106 lb.), the reduction stopped. After filtration of the catalyst, 65 g. (0.5 mole) of ethyl acetoacetate, 20 g. of anhydrous calcium sulfate, and 0.5 ml of HOAc was added. After filtration of the anhydrous calcium sulfate the solution was concentrated in vacuo till till a solid remained. The product was filtered and washed with fresh ethanol and air-dried. The yield was 84 g. (69%), m.p. 160°-162°C.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:35][C:2]2[N:24]=[C:5]3[C:6]([NH:10][CH2:11][C:12]4[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:8]=[CH:9][N:4]3[N:3]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3cccc(S(C)(=O)=O)c3)nc12)S(C)(=O)=O

Procedure:
N-(3-{[2-(3-Methanesulfonyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 3-methanesulfonyl-phenylamine; hydrochloride (39.0 mg, 0.188 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.010 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42 (dd, J=4.8, 1.5 Hz, 1H), 8.24 (s, 1H), 7.88-7.83 (m, 3H), 7.53 (d, J=4.9 Hz0, 1H), 7.29 (dd, J=7.7, 4.7 Hz, 1H), 6.96 (s, 1H), 6.72 (t, J=7.5 Hz, 1H), 6.36 (d, J=7.7 HZ, 1H), 5.36 (t, J=6.3 Hz, 1H), 4.78 (d, J=6.1 Hz, 1H), 3.33 (s, 3H), 3.10 (s, 6H). MS=502 (MH)+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[CH:11]=[CH:12][C:13]([N+:28]([O-])=O)=[C:14]([CH:27]=1)[NH:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]#[N:26].O>CN(C)C=O>[NH2:28][C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:27][C:14]=1[NH:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]=1[C:25]#[N:26]
Reactant: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(Nc2cc(F)ccc2N)sc2ccccc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 145.6 %

Procedure:
Sodium hydrosulfite (86%, 233 g) was suspended in dimethylformamide (240 ml) and the suspension was heated to 110° C. To this suspension was added dropwise at 110° C. a solution of 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (120 g), dimethylformamide (720 ml) and water (27.5 ml), which solution had been heated to 65-70° C. The reaction mixture was stirred at 110° C. for 1 hour and cooled to 20° C. Water (3.3 L) was added in 6 portions over 1 hour and the mixture was stirred at 20° C. for 1.5 hours. The precipitated crystals were filtered by suction and washed with water (2 L) to give 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carbonitrile (158 g, (wet weight)) as ocher crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][C:6]=1[CH3:15].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:42][C:43]3[CH:52]=[CH:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:44]=3)[CH:12]=2)[CH2:7][C:6]=1[CH3:15]
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)CC1=C(C)Cc2ccc(O)cc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CC1=C(C)Cc2ccc(OCc3ccc4ccccc4n3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A mixture of 2-methyl-5-hydroxy-1H-indene-3-acetic acid methyl ester (1.8 g, 8.25 mmol), powdered anhydrous potassium carbonate (1.13 g, 8.25 mmol) and 18-crown-6 (0.219 g) in acetonitrile (21 mL) is stirred at room temperature for 15 minutes. 2-(Chloromethyl)quinoline (1.6 g, 9.08 mmol) is then added and the mixture is stirred for 15 hours at 65° C. After the solvent is removed, the residue is partitioned between water and ethyl acetate. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by flash chromatography (eluant: methylene chloride-ethyl acetate) to afford 2.35 g (79%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:43]2[CH2:45][CH2:44]2)C(=O)OC(C)(C)C)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:43]2[CH2:44][CH2:45]2)[C:32]2=[N:46][CH:47]=[C:48]([C:49]#[N:50])[N:31]2[N:30]=1
Reactant: CC(C)(C)OC(=O)N(c1nc(Nc2cc(C#N)cc(N3CCN(C4COC4)C(C(=O)N4CCOCC4)C3)c2Cl)nn2c(C#N)cnc12)C1CC1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
(+/−) Tert-butyl (2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-7-cyanoimidazo[2,1-f][1,2,4]triazin-4-yl)(cyclopropyl)carbamate (40 mg, 0.057 mmol) was taken up in DCE (275 μL) and anisole (31.0 μL, 0.284 mmol) was added. The reaction was cooled to 0° C., and TFA (92 μL, 1.193 mmol) was added. The reaction was stirred at 0° C. for 30 min, then warmed to rt and stirred for 1.5 h. The solvent was removed in vacuo and the material was azeotroped 2× with toluene to remove the excess TFA. The crude material was purified by preparative HPLC to provide (+/−) 2-((2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (3.9 mg).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:23]1[CH:24]=[CH:25][C:26]2[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=[C:28]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)[C:27]=2[CH:50]=1)(=O)=O.O>COCCOC.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>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:28]2[C:27]3[CH:50]=[C:23]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:10])[CH:24]=[CH:25][C:26]=3[N:32]3[C:33]([CH3:36])=[N:34][N:35]=[C:31]3[C@H:30]([CH2:37][C:38]([NH:40][CH2:41][CH3:42])=[O:39])[N:29]=2)=[CH:44][CH:45]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccccc3C)ccc2-n2c(C)nnc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
o-Tolylboronic acid (30.1 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave) and then at 120° C. for a further 30 min (microwave). Bis(triphenylphosphine)palladium(II) chloride (12.7 mg) was added and the reaction mixture was heated at 120° C. for 30 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated and washed with water (10 ml) and brine (10 ml), dried and the solvent evaporated. The residue was chromatographed (0-5% methanol:DCM). The resulting mixture was repurified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (16.8 mg). LCMS (formate): MH+ 484/486, RT 1.14 min
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([OH:24])[CH:12]=[C:13]([Cl:23])[C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CN(C=O)C.O>[Br:32][C:12]1[C:13]([Cl:23])=[C:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][C:11]=1[OH:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O)c(Br)c(Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 70 %

Procedure:
A solution of 0.050 g (0.12 mmol) of 16 and 0.023 g (0.12 mmol) of NBS in 2 mL of DMF under argon was stirred at 25° C. for 1 day. The reaction mixture was diluted with 30 mL of water, extracted three times with diethyl ether (40 mL each), and the combined extracts were washed with brine (30 mL), dried (MgSO4), and concentrated to give 0.042 g (70% yield). This material was used in next step without purification. 1H NMR (CDCl3) δ 6.53 (s, 1H, Ar, C6-H), 1.03 (s, 9H, t-Bu), 0.96 (s, 9H, t-Bu), 0.22 (s, 6H, Me), 0.17 (s, 6H, Me); 13C NMR (CDCl3) δ 148.3 (s), 147.4 (s), 138.8 (s), 127.0 (s), 106.9 (d), 102.9 (s), 26.2 (q, t-Bu), 18.8 (s), −3.3 (q, Me), −3.5 (q, Me).