Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-fluoro-benzene as described in Example 49 and isolated as a white solid (0.072 g, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.54-8.57 (m, 2H), 7.71 (d, J=8 Hz, 1H), 7.38 (d, J=4 Hz, 1H), 7.21-7.32 (m, 3H), 7.02-7.06 (m, 2H), 6.84 (d, J=2 Hz, 1H), 6.12-6.15 (m, 1H), 5.31 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=408.3; Rt=1.22 min; HRMS (M+H)+=408.13.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([N:25]=[CH:26][N:27]=4)[C:17]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]OCC1.BrC1N2N=CN=C2C(NC2C=CC(N3CC[NH:48][CH2:47][C:46]3=[O:51])=CC=2)=NC=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:22]1[CH:21]=[C:20]([C:17]2[N:16]3[N:25]=[CH:26][N:27]=[C:15]3[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][NH:48][CH2:47][C:46]4=[O:51])=[CH:8][CH:9]=3)=[N:19][CH:18]=2)[CH:24]=[N:23]1
Reactant: c1nc2c(Nc3ccc(N4CCOCC4)cc3)ncc(-c3cn[nH]c3)n2n1
Reactant: O=C1CNCCN1c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNCCN1c1ccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)cc1

Procedure:
This compound may be prepared using methods as described for Compound 1, step 5 using 1-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (70 mg, 0.18 mmol) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.33 mmol), Pd(PPh3)4 (21 mg, 18 μmol) and NaOtBu (70 mg, 0.72 mmol) in 2 mL of 3:1 DMF/water. The reaction mixture is concentrated under vacuum and the residue is purified by silica gel column chromatography eluting with a gradient 99:1 to 90:10 DCM:NH3 (7M in MeOH). The title compound is isolated as a pale green solid (13 mg, 19%). 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 3.05 (2H, m), 3.42 (2H, s), 3.62 (2H, m), 7.32 (2H, d), 8.07 (2H, d), 8.26 (1H, s), 8.39 (1H, br s), 8.67 (1H, br s), 8.81 (1H, s), 10.05 (1H, s), 13.32 (1H, br s). LCMS: Rt 6.98 min (92.4%), m/z (APCI) 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: CC(C)CBr
Reactant: N#Cc1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Cn1cc(C#N)c(N)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Aldrich, 24.0 g, 0.222 mole), 1-bromo-2-methyl-propane (Lancaster, 36.48 g, 0.266 mole) and anhydrous potassium carbonate (Acros, 36.8 g, 0.266 mole) were suspended in 240 mL reagent grade acetonitrile and heated at 80° C. under nitrogen for 22 hours. LC/MS indicated 1 remained. Therefore, added an additional 3 mL (0.027 mole) 1-bromo-2-methylpropane and 4.25 g (0.031 mole) K2CO3. After 24 hours, the reaction was filtered and the filtrate concentrated in vacuo. The solid was stirred in 250 mL of water for 3.5 hours at room temp. The solid was filtered, washed with 50 mL diethyl ether, and dried to yield 16.28 g (45%) of a tan powder which was seen by 1H NMR to contain a mixture of 255 and 256 in approximately a 2:1 ratio. This mixture was used without further purification. Mixture of 255 and 256: mp 91.3-106; MS (ES+ calculated: 164.21; found: 165.28 M+H). HPLC (99% purity, retention times 6.920 and 7.086 minutes—Method B); 1H NMR (400 MHz, DMSO-d6) δ 8.05 and 7.51 (s, 1H), 6.50 and 5.49 (s, 2H), 3.68 (t, 2H), 2.05 (m, 1H), 0.82 and 0.81 (d, 6H).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35]#[N:36]>>[C:35]([C:30]1[CH:31]=[N:32][N:33]([CH3:34])[C:29]=1[NH:28][C:11]([C:13]1[C:14]2[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=2[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=1)=[O:12])#[N:36]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Reactant: Cn1ncc(C#N)c1N
Product: CCc1cc2c(C(=O)Nc3c(C#N)cnn3C)cnc(OC(F)F)c2o1
Yield: 52.3 %

Procedure:
Starting from 7-difluromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (65 mg). Purification by column chromatography on silica eluting with 2-3% methanol in dichloromethane followed by trituration with diethyl ether afforded the title compound as a white solid (50 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(O[CH:17]=[CH:18][CH:19]=[CH2:20])(=O)C.C([O-])(=O)C.[Na+].O=O>C(O)(=O)C.CN(C)C=O>[CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC=COC(C)=O
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: O=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
15.8 parts by weight naphthoquinone and 13.5 parts by weight of 1-acetoxybutadiene in 50 parts by volume of dimethylformamide and 1 part by volume of acetic acid are stirred for 6 hours under nitrogen at 45° - 50° C. 0.4 part by weight of sodium acetate is then added, oxygen is passed in and the batch is stirred for 2 hours at 120° C. After cooling, the anthraquinone which has precipitated is filtered off and washed with dimethylformamide. 18.2 parts by weight (91% of theory) of anthraquinone of melting point 284° C are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([C@@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])[O:17][N:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]=[C:18]([C@@H:20]([NH2:22])[CH3:21])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Cl)cc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
2,2,2-Trifluoroacetic acid (4 mL, 52 mmol) was added to a solution of (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (0.613 g, 1.89 mmol) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with chloroform (3×30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (500 mg, yellow oil). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 4.37 (q, J=6.9 Hz, 1H), 1.62 (d, J=6.9 Hz, 3H). MS m/z 224.0 (M+H)+; Rt-0.56 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][C@@:16]1([OH:32])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30].[CH:34]1([C:37](OC2C([2H])([2H])C([2H])([2H])C3C(=CC=C(F)C=3)C2(CCN(CCCC2NC3C=CC=CC=3N=2)C)C(C)C)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([O:32][C@:16]2([CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH3:33])[CH2:25][C:24]([F:27])([F:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=3)[C@@H:17]2[CH:29]([CH3:31])[CH3:30])=[O:38])[CH2:36][CH2:35]1
Reactant: [2H]C1([2H])c2cc(F)ccc2C(CCN(C)CCCc2nc3ccccc3[nH]2)(C(C)C)C(OC(=O)C2CC2)C1([2H])[2H]
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@@]1(CCN(C)CCCc1nc2ccccc2[nH]1)OC(=O)C1CC1

Procedure:
Compound 304 is prepared from 35d in a manner analogous to that of Example 6 for compound 704a.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[O:9][C:10]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[N:15][N:16]=[CH:17]4)=[CH:11][C:3]=12.[Si]([O:29][CH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32][CH2:31]1)(C(C)(C)C)(C)C>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:39]2[CH:38]=[N:37][N:36]([C@H:33]3[CH2:34][CH2:35][C@H:30]([OH:29])[CH2:31][CH2:32]3)[CH:40]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[N:15][N:16]=[CH:17]4)[O:9][C:4]=12
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnncc34)oc12
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cccc4cnncc34)oc12

Procedure:
The title compound was prepared from 4-iodo-2-(phthalazin-5-yl)furo[2,3-c]pyridin-7-amine and 1-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole by a procedure analogous to Example 365, Step F. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.80 (d, J=1.26 Hz, 1H), 8.65 (d, J=7.33 Hz, 1H), 8.25-8.35 (m, 2H), 8.20 (t, J=7.80 Hz, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 6.54 (br s, 2H), 4.68 (d, J=4.29 Hz, 1H), 4.18 (tt, J=3.73, 11.43 Hz, 1H), 3.48-3.59 (m, 1H), 2.07 (br d, J=12.10 Hz, 2H), 1.81-2.01 (m, 4H), 1.31-1.44 (m, 2H); MS (ESI): 427.01 [M+H]+; HPLC tR=2.38 min (ZQ3: polar—5 min).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].C1CCN2C(=NCCC2)CC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH:48]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1>CC#N>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47]/[CH:48]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1
Reactant: O=CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a 0° C. suspension of LiCl (55.4 mg, 1.306 mmol) in MeCN (2 mL) under N2 was added trimethyl phosphonoacetate (0.188 mL, 1.306 mmol) and DBU (0.197 mL, 1.31 mmol). The reaction was stirred at 0° C. for 30 minutes, and then 3-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (300 mg, 0.871 mmol) was added. The reaction was stirred at rt for 2 h and concentrated in vacuo. The residue was diluted with Et2O, washed with 1 N aq. HCl, satd aq. NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (300 mg, 86% yield) as a white solid. LCMS, [M+NH4]+=418.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.03-6.93 (m, 3H), 5.86 (dt, J=15.7, 1.5 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 3.65-3.59 (m, 1H), 2.23-2.15 (m, 2H), 2.09-1.98 (m, 5H), 1.89-1.84 (m, 2H), 1.75-1.58 (m, 8H), 1.37-1.31 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][CH2:9][C:5]2[N:4]([CH3:3])[CH:8]=[CH:7][N:6]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cn1ccnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccnc1COc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Sodium hydride (0.30 g as an 80% dispersion by weight in oil) was added to a solution of 1-methyl-2-hydroxymethylimidazole (1.12 g) in tetrahydrofuran (30 ml) and the mixture stirred at room temperature for one hour. A solution of 4,6-dichloropyrimidine (1.48 g) in tetrahydrofuran (10 ml) was added to the reaction mixture dropwise over 30 minutes and the mixture stirred at room temperature for 3 hours and evaporated. The residue was taken up in dichloromethane and the solution extracted into 2M hydrochloric acid. The acidic layer was washed with dichloromethane, basified with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane. The organic layer was dried over Na2SO4 and evaporated to give the title compound (1.2 g), m.p. 126°-128° C. This compound was used directly in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.CCCCCC.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COCOc1cccc(OCOC)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 1,3-bis{[(methyloxy)methyl]oxy}benzene (Intermediate 79, 2.19 g) in dry tetrahydrofuran (10 ml) at room temperature BuLi 1.6M in hexane (8.29 ml, 13.26 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (2.263 g, 16.57 mmol) in dry tetrahydrofuran (10 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml) and extracted with ethyl acetate (2×30 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound as a light yellow oil (1.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:15]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Sc3ccccc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2nccc(S(=O)c3ccccc3)c2cc1OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6,7-dimethoxy-4-phenylsulfanyl-quinoline (Step a, 1.0 g, 3.4 mmol) in CH2Cl2 (30 mL) at −78° C., 3-chloroperoxybenzoic acid (0.64 g, 3.7 mmol) was added in CH2Cl2 dropwise slowly. The reaction was stirred at −78° C. for 2 h. The solution was poured into saturated NaHCO3 and extracted with CH2Cl2 3×. The combined organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography with (70-100% EtOAc/Hexane) to give the titled compound as a white solid. MS (ESI, pos. ion) m/z: 314.4 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[N:7]1([CH2:2][C:3]([O:5][CH3:6])=[O:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.40 ml of methyl bromoacetate was added dropwise to a mixture of 0.25 g of indoline, 2 ml of dimethylformamide and 0.87 g of anhydrous potassium carbonate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.30 g of the title compound having Rf=0.63 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[F:9][CH:8]([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]=[O:19]
Reactant: FC(F)c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccccc1C(F)F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
After dissolving 1-bromo-2-difluoromethylbenzene (3.23 g) in tetrahydrofuran (65 ml), the mixture was cooled to −78° C. After then adding n-butyllithium (2.64 M solution in hexane, 6.5 ml) and stirring for 30 minutes, N,N-dimethylformamide (2.4 ml) was added and stirring was continued for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (991 mg).
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][N:13]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:8]1[C:9]([C:14]([O:16][CH3:17])=[O:15])=[N:10][CH:11]=[CH:12][N:13]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: COC(=O)c1nccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1nccnc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
107 ml of 1,2-dimethoxyethane were aerated with argon, and 597 mg (0.51 mmol) of Pd(PPh3)4 and 2.24 g (10.3 mmol) of methyl 3-brompyrazine-2-carboxylate were added. After 10 min, 3.9 g (15.45 mmol) of 2-(tert-butoxycarbonylaminomethyl)-phenylboronic acid and finally 10.7 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 661 mg (19%) of a viscous oil were obtained. MS (ES+): m/z=344 (M+1), 288 (M−55). 1H-NMR (CDCl3): δ=8.78 (1H, d, J=2.4 Hz), 8.67 (1H, d, J=2.4 Hz), 7.54-7.14 (4H, m), 5.11 (1H, br s), 4.22 (2H, d, J=5.9 Hz), 3.79 (3H, s), 1.38 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)[C:4](=[O:17])[CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>C(O)(=O)C>[Cl:25][C:3]1[C:4](=[O:17])[N:5]([CH2:9][C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[CH:12][N:11]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Cc1cnc(Cn2c(C)cc(O)cc2=O)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1cnc(Cn2c(C)cc(O)c(Cl)c2=O)cn1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (1.00 g, 4.3 mmol) in glacial acetic acid (10 mL) was added NCS (0.79 g, 5.94 mmol). The reaction mixture stirred at 60° C. for 6 hours. The solvent was removed under reduced pressure and the resulting residue was triturated with ethyl acetate. The desired product was filtered and dried (0.80 g, 69%). 1H NMR (CD3OD, 400 MHz) δ 8.47 (s, 1H), 8.42 (s, 1H), 6.08 (s, 1H), 5.36 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 266.0691 (M+H calculated for C12H13N3O2Cl requires 266.0691).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=O)=[C:8]([CH3:20])[C:7]([O:21][CH3:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O>N1C=CC=CC=1>[OH:3][C:1]1[C:4]2[C:9](=[C:8]([CH3:20])[C:7]([O:21][CH3:22])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:2]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1C
Temperature: 150 °C
Yield: 95 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)-amide (96) in pyridine (15 mL) was added 2.5 equivalent of freshly grounded KOH along with water (200 μL). The mixture was heated by microwave irradiation at 150° C. for 30 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give the title compound (1.8 g, 95%): m/z=299 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[C:6]([I:14])[CH:5]=1>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([I:14])[C:7]([CH3:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(I)c(C)c([N+](=O)[O-])c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(C)c(I)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 67.3 %

Procedure:
To a solution of 3-iodo-4-methyl-5-nitro-benzoic acid methyl ester (2.0 g, 6.23 mmol) in a mixture of THF (40 mL) and methanol (1 mL) was added SnCl2 dihydrate (4.22 g, 18.69 mmol). The reaction mixture was stirred at 60° C. for six hours, then cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1.22 g (67%) of 3-amino-5-iodo-4-methyl-benzoic acid methyl ester.