Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[N:70][C:71]([N:74]5[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]5)=[CH:72][CH:73]=4)[CH:66]=3)[N:61](S(C3C=CC(C)=CC=3)(=O)=O)[CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:54]1[CH:58]=[C:57]([C:59]2[C:67]3[C:62](=[N:63][CH:64]=[C:65]([C:68]4[CH:69]=[N:70][C:71]([N:74]5[CH2:75][CH2:76][NH:77][CH2:78][CH2:79]5)=[CH:72][CH:73]=4)[CH:66]=3)[NH:61][CH:60]=2)[CH:56]=[N:55]1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)nc5)cc34)cn2)cc1
Yield: 98.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (55 mg, 0.09 mmol) was hydrolyzed with lithium hydroxide (20 mg, 0.45 mmol) in THF/methanol/water (2/1/1 mL) to yield 40 mg (100% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.51-8.50 (d, 1H), 8.43 (s, 1H), 8.25-8.15 (dd, 1H), 7.91-7.86 (d, 2H), 7.68 (s, 1H), 7.27-7.21 (m, 3H), 7.14-7.12 (m, 3H), 4.50-4.40 (t, 2H), 3.97-3.94 (t, 4H), 3.43-3.34 (t, 4H), 3.20-3.18 (t, 2H). MS: m/z=450.4 (M+1), HPLC: 92.83% in method A.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.ClC[CH2:20][CH2:21][S:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[N:25]1([S:22]([CH2:21][CH2:20][CH2:2][O:3][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:15][CH2:16][N:17]=4)[C:10]([NH2:14])=[N:11][C:12]=3[CH:13]=2)(=[O:24])=[O:23])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)N=C(N)N1CCN=C21
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Agent: Br
Product: NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12

Procedure:
The procedure used for the preparation of Example 24, Step 2 was used to prepare the title compound from 5-amino-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol (Intermediate I) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). Yield 190 mg (61%). Rf=0.68 in 10% MeOH/CH2Cl2, HPLC MS RT=1.13 min, MH+=394.4.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.C(O)C.Cl>C1(C)C=CC=CC=1>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: CCc1ccc(-c2ccc(N(C(C)=O)c3ccc(C)cc3)cc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccc(-c2ccc(Nc3ccc(C)cc3)cc2)cc1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 19.96 g of the thus obtained N-acetyl-N-(4-methylphenyl)-4'-ethyl-[1,1'-biphenyl]-4-amine were added 150 ml of ethanol and 150 ml of concentrated hydrochloric acid. The reaction mixture was refluxed with stirring for 7 hours and then added to 1 l of ice water. The reaction mixture was then extracted with toluene and the obtained organic portion was washed with water two times, with a saturated aqueous solution of sodium hydrogencarbonate one time, and then with water two times, and dried by use of magnesium sulfate, and condensed under reduced pressure, whereby brown crystals were obtained. The thus obtained product was subjected to a silica gel column chromatography by use of toluene as an eluent, and recrystallized from a mixed solvent of n-hexane and toluene, whereby 4'-ethyl-N-(4-methylphenyl)-[1,1'-biphenyl]-4-amine (Aminobiphenyl Compound No. 2-62 in Table 3) was obtained in the form of colorless plates with a yield of 15.84 g (91.0%). The melting point of the product was 132.5° C. to 133.0° C.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][SH:8])[C:3]([NH2:5])=[S:4].[Na].Cl.Cl[CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18]>C(O)C>[CH3:1][N:2]([CH2:6][CH2:7][S:8][CH2:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH3:18])[C:3]([NH2:5])=[S:4]
Reactant: Cc1[nH]cnc1CCl
Reactant: CN(CCS)C(N)=S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCN(C)C(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
N-Methyl-N1 -(2-mercaptoethyl)thiourea (3.85 g) in dry ethanol (10 ml) was added to a solution of sodium (1.18 g) in dry ethanol (50 ml) and the mixture was stirred at room temperature for one hour. 4-Chloromethyl-5-methylimidazole hydrochloride (4.29 g) was added portionwise over one hour to this stirred mixture at room temperature. The mixture was stirred at room temperature for a further hour and heated under reflux for 1/2 hour, cooled and filtered. The filtrate was evaporated to an oily solid which was recrystallised from water to give N-methyl-N1 -[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (3.2 g) m.p. 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23](OCC)=[O:24])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH:23]=[O:24])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Ethyl 1-[(4-methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (430 mg) was dissolved in tetrahydrofuran (10 mL), and the mixture was cooled to −78° C. A 1.5 mol/l solution (3.36 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), tetra-n-propylammonium perruthenate (39 mg), N-methylmorpholine N-oxide (227 mg) and molecular sieves 4A powder (500 mg) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown oil (yield 249 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:28][C:29]2([CH3:32])[CH2:31][O:30]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH3:28][C:29]1([CH2:32][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH2:31][O:30]1
Reactant: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(Cn2nc(-c3ccc(OC(F)(F)F)cc3)oc2=O)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of 5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (3.18 g, 12.92 mmol) prepared in Reference Example 49, (2-methyl-2-oxiranylmethyl) toluene-4-sulfonate (4.80 g, 19.38 mmol), potassium carbonate (2.14 g, 15.50 mmol) and sodium iodide (2.90 g, 19.38 mmol) in DMF (30 ml) was stirred at room temperature for 24 hours, and then at 60° C. for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to afford 3-(2-methyl-2-oxiranylmethyl)-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (2.37 g, yield 58%) as a colorless crystalline powder.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Cl:29][Sn]Cl.C(O)C.Cl>O>[ClH:29].[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Sn]Cl
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(N)cc3)nc(=O)c1-2
Yield: 60.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidin-4-one (1.38 g, 3.9 mmol), SnCl2.2H2O (2.64 g, 11.72 mmol), ethanol (24 ml) and water (10 ml) was added concentrated HCl (14.5 ml). The reaction mixture was refluxed for 2 hours, cooled, and the product was collected by filtration and dried in vacuo to afford 0.85 g (67%) of 1-cyclopentyl-3-ethyl-6-(4-aminophenyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride 1/3 hydrate, m.p. 279° C. (dec.).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH:33]1[CH2:35][CH2:34]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:39]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:39])=[O:32])[CH:20]=[C:19]1[CH:33]1[CH2:34][CH2:35]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-cyclopropyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 266, 2.64 g, 5.18 mmol) following the procedure described for Intermediate 19. The desired product was obtained as an orange foam (2.33 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:25]=[CH:24][C:10]([NH:11][CH:12]=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[OH:21][C:19]1[C:24]2[C:10](=[CH:9][CH:8]=[C:7]([N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])[CH:25]=2)[N:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=CNc1ccc(N2CCOC2=O)cc1)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(N3CCOC3=O)cc2c1O
Temperature: 235 °C
Yield: 42.6 %

Procedure:
To a flask containing diethyl 2-{[4-(2-oxo-1,3-oxazolidin-3-yl)anilino]-methylene}-malonate (0.46 g) is added diphenyl ether (6 mL). The reaction mixture is heated from room temperature to 235° C. over 2 hours under a flow of argon gas. After 1 hour at 235° C. the reaction is cooled to room temperature, diluted with diethyl ether and filtered. The collected precipitate is washed repeatedly with diethyl ether then dried in vacuo to give 0.17 g of ethyl 4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxylate as a tan solid.
Reaction SMILES: CS[C:3]1[C@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[N:4]=1.[CH2:25]([NH2:28])[C:26]#[CH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.Cl>CCOCC>[CH3:27][C:26]1[N:4]2[C:5]3[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=3[CH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]2=[N:28][CH:25]=1
Reactant: CSC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1
Reactant: C#CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Cc1cnc2n1-c1ccccc1CCC2NC(=O)OCc1ccccc1
Yield: 70.1 %

Procedure:
Combine benzyl N-[(3R)-2-methylsulfanyl-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (500 mg, 1.47 mmol), propargylamine (197.28 μL, 2.94 mmol), and p-toluenesulfonic acid monohydrate (30 mg, 157.71 μmoles) in phenyl ether-biphenyl mixture (2 mL, 6.53 mmol) (Dowtherm A) and stir the mixture for approximately 45 minutes at 180° C. Cool the reaction, and add ether (20 mL), then 2M HCl (20 mL). Stir for a few minutes, remove the aqueous layer, and extract the organic layer with 2N HCl (2×). Combine the aqueous layers and basify with ammonium hydroxide (28%) until alkaline. Collect the precipitate by filtration, wash it with water, and dry it in a vacuum oven. Purify the precipitate by flash chromatography (50% of a 5% solution of ammonia/methanol (2M) in dichloromethane to 90% of the 5% solution) to give the title compound (358 mg, 70%) as an off white solid: MS (m/z): 348 (M+1). Retention time for Isomer 1 (S Isomer)=3.3 min; Isomer 2 (R Isomer)=3.7 min. (Chiralpak AD-H column; 100% EtOH with 0.2% dimethylethylamine; flow rate 1.0 mL/min; 225 nM). Chiral analysis indicates about 20% racemization.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O.C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2[CH:11]=[C:10]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CO[C@H]1CC[C@H](n2c(=O)c(Br)cc3c(C)nc(N)nc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@H](OC)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
To a vial containing 2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.20 mmol), 2-methoxy-5-pyridineboronic acid (37.5 mg, 0.245 mmol) and cesium carbonate was added PdCl2(dppf)1:1 w/CH2Cl2 followed by 5:1 dimethoxyethane:water (3 mL, degassed by bubbling with argon). The vial was capped and heated in the microwave for 30 minutes at 100° C. The reaction mixture was concentrated and the crude product was purified by flash chromatography eluting with chloroform/methanol (0-5%). The fractions containing the desired product were concentrated and the solids were triturated with methyltertbutyl ether to afford 2-amino-8-(trans-4-methoxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (33 mg, 40%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][CH2:8][OH:9])=[O:4].[Li][CH2:21][CH2:22][CH2:23]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[CH2:23]([O:9][CH2:8][CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH:22]=[CH2:21]
Reactant: COc1cccc(C(CCO)NC(=O)C(F)(F)F)c1
Reactant: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOCCC(NC(=O)C(F)(F)F)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.8 %

Procedure:
Step R (2): 2,2,2-Trifluoro-N-(3-hydroxy-1-(3-methoxyphenyl)propyl)acetamide from step R (1) (1.99 g, 7.18 mmol) was dissolved in THF (20 mL) and chilled to −78° C. n-BuLi (5.76 mL, 14.4 mmol, 2.5 M in hexanes) and DMPU (1.73 mL, 14.4 mmol) were added and the resulting mixture was stirred for 45 min. Allyl bromide (3.04 mL, 36 mmol) was added. The mixture was warmed to rt and then heated to reflux for 3 days. The mixture was quenched with saturated NH4Cl. After 15 min, the mixture was diluted with 1 N NaOH and the aqueous mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica-gel column chromatography (0%-25% EtOAc/Hexanes) afforded 610 mg (27% yield) of N-(3-(allyloxy)-1-(3-methoxyphenyl)propyl)-2,2,2-trifluoroacetamide as a viscous yellow oil. LC-MS (M+H)+=318.37; 1H NMR (300 MHz, CDCl3) δ ppm 1.89-2.01 (m, 1H) 2.14-2.29 (m, 1H) 3.34-3.52 (m, 2H) 3.77 (s, 3H) 3.91 (d, J=5.86 Hz, 2H) 5.10-5.30 (m, 3H) 5.79-5.95 (m, 1H) 6.70-6.82 (m, 3H) 7.19-7.29 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:13]=[O:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A solution of (3,4-dinitro-phenyl)-methanol (95.3 g, 481 mmol) in methylene chloride (500 mL) was added all at once to a suspension of pyridinium chlorochromate (156 g, 722 mmol) in methylene chloride (900 mL). The mixture was stirred at room temperature for 1.5 h and then ether (1500 mL) was added. The supernatant was decanted from the resulting black gum, and the insoluble residue was washed thoroughly with methylene chloride (3×250 mL). The combined organic solution were filtered through a pad of florisil to afford a light bright yellow clear solution. Solvents were removed in vacuo and the residue was purified by silica gel chromatography using methylene chloride as eluent to afford the title compound as a yellow solid (71%). 1H-NMR (CDCl3, 300 MHz) δ 8.45 (d, J=1.5 Hz, 1H), 8.28 (dd, J=8.1, 1.5 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H). 13CNMR (CD3OD, 125 MHz) δ 187.7, 139.2, 134.2, 126.2, 125.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (46.6 mg, 35%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[N:19]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: COc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)n1

Procedure:
Prepared according to Procedure E using 2,4-dichloro-5,7-difluoro-3-methylquinoline (250 mg, 1.01 mmol) and 2-methoxy-6-(tributylstannyl)pyridine to give 4-chloro-5,7-difluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([NH2:14])[CH:11]=2)[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:26])([F:27])[F:28])[CH:21]=1
Reactant: C[C@@H](OCc1cc(Cl)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccc(F)cc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Yield: 115.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (50 mg) prepared according to the same procedures as Preparation 18 in 1,2-dimethoxyethane (0.5 ml) were sequentially added 2-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (72 mg) prepared according to the same procedures as Preparation 22, a 2M aqueous solution of sodium carbonate (0.25 ml), tricyclohexylphosphine (9.3 mg) and palladium (II) acetate (3.7 mg) at room temperature, and the mixture was stirred at 100° C. for 2 hours. This reaction mixture was cooled to room temperature, filtered through Celite, and subjected to elution with ethyl acetate. The filtrate was extracted with ethyl acetate, the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (79 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C[Si]([C:13]#[CH:14])(C)C.[OH-].[Na+].Cl>C(N(CC)CC)C.CO.[Cu]I.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:13]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)#[CH:14]
Reactant: Cc1cccc(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1cccc(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 341.4 %

Procedure:
A solution of 2-bromo-6-methylpyridine (0.5 g, 2.9 mmol) and (trimethylsilyl)acetylene (0.29 g, 2.9 mmol) in triethylamine (15 mL) is purged with argon. Copper(I) iodide (11 mg, 0.06 mmol) and (PPh3)2PdCl2 (42 mg, 0.06 mmol) are added and the reaction is stirred under argon at room temperature for 2 h. The solvent is removed in vacuo and the residue is diluted in ethyl acetate (50 mL) and water (50 mL). The organic is separated and washed with brine. The solvent is removed to afford a dark oil. This oil is diluted in methanol (50 mL) and treated with a 1 N sodium hydroxide solution (10 mL) and stirred for 3 h at room temperature. The aqueous is neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The solvent is removed in vacuo to afford a dark oil that is purified by SiO2 column chromatography to yield 1.16 g (24%) of the title compound as a light yellow oil.