Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]([O:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=1>O1CCCC1>[C:14]1([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[O:7][C:5]([C@H:4]2[C@H:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[O:29]2)=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2O[C@H]2C(=O)O[C@@H]2CCCC[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A 5.0-L three-necked flask equipped with a stirrer, a gas bubbler, a thermometer, an addition funnel and condenser was charged with 100 g (3.33 mole) of NaH (80% in mineral oil), and triturated with 3×500 mL=1.5 L of hexane. Each portion of hexane was decanted when the NaH had settled. Under an argon atmosphere, 1.5 L of tetrahydrofuran was added followed by a solution of 568 g (2.247 mole) of (-)-(1R,2S)-2-phenylcyclohexyl chloroacetate, 352 g (2.589 mole) of anisaldehyde and 250 mL of tetrahydrofuran over 0.5 hour via addition funnel. A vigorous evolution of H2 gas ensued along with an exotherm to about 55°. After the initial reaction subsided, the mixture was then stirred under argon at ambient temperature overnight. The mixture was heated at 55-60° for 1 hour and then quenched into 8.0 L of ice water. The pH was adjusted to 7 with 390 mL of 3N H2SO4 and the resulting mixture was extracted first with 4 L followed by 2×2 L for a total of 8.0 L of methylene chloride. The combined organic layers were dried (Na2SO4) and evaporated in vacuo to an oily, partially solid residue which on crystallization from 0.5 L of (9:1) hexanes-ethyl acetate afforded colorless needles. These crystals were collected by filtration, washed with 2×200 mL=400 mL of 9:1 hexanes-ethyl acetate followed by 2×500 mL=1.0 L of cold hexanes and finally dried in vacuo to afford 403 g (51%) of the title compound, m.p. 146-148° C., [α]D20 =-146°(c=1; CHC13).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH3:5][C:6]1([CH3:17])[CH2:15][CH:14]([CH3:16])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[NH:7]1>C(O)C>[OH:4][CH:2]([CH3:3])[CH2:1][N:7]1[CH:8]2[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:14]([CH3:16])[CH2:15][C:6]1([CH3:5])[CH3:17]
Reactant: CC1CO1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCO
Product: CC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
1-(2'-hydroxypropyl)-2,2,4-trimethyl decahydroquinoline was prepared by the reaction of 30.2 grams (0.52 mole) of propylene oxide with 90.7 grams (0.5 mole) of 2,2,4-trimethyl decahydroquinoline of about 75% cis structure in the presence of 3 grams of ethanol at 170° C. for 49 hours. The reaction mix was distilled using a 4 inch Vigreaux column to yield 73.1 grams of the desired product, boiling at 93° to 96° C. at 0.26 mm Hg. The NMR and mass spectrometer spectra were consistent with the desired product. The formula C15H29NO has calculated contents of 75.25% carbon, 12.21% hydrogen, and 5.85% nitrogen and the measured contents were 75.42% carbon, 12.77% hydrogen, and 5.62% nitrogen.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]1(B(O)O)[CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:15]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)C1CCC1
Reactant: O=[N+]([O-])c1ccc(I)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 47.3 %

Procedure:
A mixture of 2-iodo-5-nitrobenzotrifluoride (4.62 g), cyclobutylboronic acid (4.15 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (4.15 g), cesium carbonate (22.6 g), toluene (67.0 mL) and water (33.0 mL) was stirred in a sealed tube at 80° C. for 6 hours. After cooling the reaction mixture to room temperature, extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-94:6) to give 1-cyclobutyl-4-nitro-2-(trifluoromethyl)benzene as a pale yellow oil (1.69 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(C(C)C)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: CC(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-isopropyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 342.0 ([M−H]−).
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:60][CH:61]([F:78])[CH2:62][NH:63][CH:64]1[CH2:70][CH2:69][C:68]2=[C:71]([NH2:77])[C:72]([O:75][CH3:76])=[CH:73][CH:74]=[C:67]2[CH2:66][CH2:65]1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:77][C:71]2[C:68]3[CH2:69][CH2:70][CH:64]([NH:63][CH2:62][CH:61]([F:78])[F:60])[CH2:65][CH2:66][C:67]=3[CH:74]=[CH:73][C:72]=2[O:75][CH3:76])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCC(NCC(F)F)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (Single Diasteromer B). 2nd peak elution from HPLC purification. LC/MS (ESI): 573.25. 1H NMR (400 MHz, DMSO, d6) δ 9.14 (m, 2H), 7.15 (m, 2H), 6.87 (m, 1H), 6.41 (td, 1H), 3.70 (s, 3H), 3.56 (m, 3H), 3.42 (m, 2H), 3.16 (s, 3H), 2.91 (m, 4H), 2.74 (m, 1H), 2.54 (m, 2H), 1.67 (m, 1H), 1.34 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.C([SiH2][O:30][C:31](C)(C)[C@H:32]([NH2:48])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][Si](C(C)(C)C)(C)C)=[CH:36][CH:35]=1)(C)(C)C.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:48][C@@H:32]([CH2:31][OH:30])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@H](N)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H](CO)Cc3ccc(O)cc3)c21
Temperature: 120 °C
Reaction time: 3 h

Procedure:
350 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 600 mg (R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-ethylamine and 350 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.2 hours. Then the reaction mixture is evaporated to dryness. The residue is suspended in water/acetonitrile/trifluoroacetic acid and stirred for 3 hours at ambient temperature. The reaction mixture is evaporated to dryness and the diastereomers are separated by preparative HPLC (method D). Analytical HPLC-MS (method E): Diastereomer 1: RT=1.20 min; Diastereomer 2: RT=1.25 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][Cl:18])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][Cl:18]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)c(N)cc1OCCCl
Temperature: 40 °C
Yield: 98.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 3.76 g (13.5 mmol) of 5-methoxy-4-(2-chloroethoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-16, 40 mL of methanol, and 0.4 g of 5 wt. % palladium/carbon (containing 49% water). The resulting mixture was heated to 40° C. under stirring, and further heated to the same temperature for 4 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 3.27 g (isolated yield: 98.1%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(2-chloroethoxy)anthranilic acid as a white crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](I)[C:3]=1[OH:9].CCN(CC)CC.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C([O-])(O)=O.[Na+]>CN(C=O)C.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>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:9][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1c(Cl)ccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nccc(Cl)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a solution of 4-chloro-3-hydroxy-2-iodopyridine (1.04 g, 4.10 mmol) in DMF (10 mL) was added (Ph3P)2PdCl2 (0.140 g, 0.20 mmol), CuI (0.152 g, 0.80 mmol) and Et3N (0.496 g, 4.90 mmol). The mixture was stirred at room temperature for one hour. A solution of 1-Boc-2-(S)-ethynylpyrrolidine (0.80 g, 4.10 mmol), from step 1c above, in DMF (10 mL) was added and the mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated NaHCO3 and washed with Et2O (4×100 mL). The combined organic extracts were washed with brine/H2O (1/1 400 mL), dried (MgSO4), and concentrated. The crude product was chromatographed (silica gel; CH2Cl2 /MeOH, 90:10) to afford the title compound as a brown oil (0.180 g, 14%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 1.95-2.10 (m, 4H), 3.10-3.25 (m, 2H), 4.90-5.10 (m, 1H), 6.65 (s, 1H), 7.10 (br s, 1H), 8.38 (br s, 1H); MS (DCI/NH3) m/z: 323 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[N:33]([CH2:34][C@H:35]2[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]2)[C:19]2[C:20]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([Cl:32])[CH:31]=3)=[N:21][C:22]([C:24]#[N:25])=[CH:23][C:18]=2[N:17]=1.[F-].[K+].CCN(C(C)C)C(C)C>CCOC(C)=O.CS(C)=O>[Cl:32][C:30]1[CH:31]=[C:26]([C:20]2[C:19]3[N:33]([CH2:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]4)[C:16]([N:7]4[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]4[CH3:1])=[N:17][C:18]=3[CH:23]=[C:22]([C:24]#[N:25])[N:21]=2)[CH:27]=[N:28][CH:29]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added (R)-tert-butyl 3-methylpiperazine-1-carboxylate (purchased from Astatech) (180 mg, 0.899 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (200 mg, 0.450 mmol, Preparative Example 3.1), potassium fluoride (78 mg, 1.349 mmol), DMSO (1 ml) and DIEA (0.236 ml, 1.349 mmol). The reaction vial was capped and heated to 100° C. overnight. The mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give (R)-tert-butyl 4-(4-(5-chloropyridin-3-yl)-6-cyano-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-methylpiperazine-1-carboxylate. MS ESI calc'd. for C30H38ClN7O2 [M+H]+ 564. found 564.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:21]([CH3:24])=[N:22][N:23]=4)[C:15]=3[CH:14]=[C:13]2[CH3:25])=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:24][C:21]1[N:20]2[C:15]3[CH:14]=[C:13]([CH3:25])[N:12]([CH2:11][C:10]4[CH:26]=[CH:27][C:7]([OH:6])=[CH:8][CH:9]=4)[C:16]=3[CH:17]=[CH:18][C:19]2=[N:23][N:22]=1
Reactant: COc1ccc(Cn2c(C)cc3c2ccc2nnc(C)n23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(O)cc1

Procedure:
1.0 M Boron tribromide in DCM (0.54 mL, 0.54 mmol, Aldrich) was added to a solution of 6-(4-methoxybenzyl)-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (42 mg, 0.137 mmol, from Example 34) in DCM (4 mL) at −78° C., and the reaction was allowed to slowly reach room temperature. The reaction was quenched by the addition of water, followed by saturated NaHCO3 solution. DCM was removed in vacuo and the mixture was diluted with MeOH, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (27 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=9.7 Hz, 1H), 7.14 (d, J=9.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.56 (s, 1H), 5.23 (s, 2H), 2.95 (s, 3H), 2.45 (s, 3H); LCMS (M+H)+: 293.1.
Reaction SMILES: C1([C:6]2[C:14]3[C:9](=[CH:10][C:11](C(NC4(C(NC5C=CC(/C=C/C(O)=O)=C(OCC)C=5)=O)CCC4)=O)=[CH:12][CH:13]=3)[N:8](C)[C:7]=2[C:40]2C=CC=CN=2)CCCC1.[Li]CCCC.CI>C1COCC1>[CH3:40][C:7]1[NH:8][C:9]2[C:14]([CH:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCOc1cc(NC(=O)C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5ccccn5)n(C)c4c3)CCC2)ccc1/C=C/C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 2-bromoindole derivative 3-1 (1.009 g, 3.00 mmol, prepared as described in Example 12 of WO 03/010141) was dissolved in anhydrous THF (25 mL) under an argon atmosphere and the solution cooled to −78° C. n-BuLi (2.0 M in hexane, 1.60 mL, 3.20 mmol) was added dropwise and the mixture stirred for 15 min. MeI (0.37 mL, 2.00 mmol) was added and stirring was continued for an additional 30 min. The reaction mixture was then warmed up to RT and volatiles removed under reduced pressure. The residue was dissolved in TBME (100 mL) and the solution washed with brine (2×25 mL). The extract was dried (MgSO4), concentrated under reduced pressure and the residue purified by flash chromatography using 0–15% EtOAc in hexane as eluent. The desired 2-methylindole derivative 18-1 was obtained as a waxy solid (0.658 g, 80% yield): MS-ES m/z 272.1 (MH+). The methyl ester 18-1 was saponified in the usual way (NaOH/DMSO) to give the corresponding carboxylic acid 18-2 in 96% yield: MS-ES m/z258.1 (MH+).
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>O1CCCC1>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(Br)ccc1N(CCO)Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of 2-[benzyl-(4-bromo-2-nitro-phenyl)-amino]-ethanol (19.52 g, Reference Example 9) and triethylamine (7.8 ml) in anhydrous tetrahydrofuran (95 ml), at 25° C., was treated dropwise with methanesulphonyl chloride (4.75 ml). After stirring for 4 hours at 25° C. a further portion of methanesulphonyl chloride (4.75 ml) was added and stirring was continued for a further 16 hours at 25° C. The reaction mixture was treated with water (100 ml), the organic phase was separated and the aqueous phase was extracted three times with ethyl acetate (150 ml). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), then three times with distilled water (50 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. to give the title compound (25.41 g) as a brown oil. 1H NMR, 300 MHz, (CD3)2SO: δ3.1 (s, 3H); 3.4 (t, 2H); 4.2 (t, 2H); 4.4 (s, 2H); 7.2(m, 5H); 7.4 (d, J=8 Hz, 1H); 7.7 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 430 and 428 (5%), 321 and 319 (20%), 91 (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[C:19]([C:23]([NH:25][C:26]4[C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:34][CH3:35])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=3[C:11]=2[N:10]=1.[Na+].[I-:37].II>O1CCOCC1.ClCCl.CO.[Cu]I>[CH2:34]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH3:33])[C:26]=1[NH:25][C:23]([C:19]1[C:13]2[CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[I:37])=[N:10][C:11]=3[C:12]=2[N:21]([CH3:22])[N:20]=1)=[O:24])[CH3:35]
Reactant: [I-]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3Br)nc1-2
Agent: [Cu]I
Agent: II
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3I)nc1-2
Temperature: 150 °C
Yield: 46.9 %

Procedure:
To a solution 8-[(2-bromophenyl)amino]-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (68 mg, 0.129 mmol) in dioxane (0.5 mL) in a sealed tube, NaI (38 mg, 0.257 mmol), CuI (1.2 mg, 0.006 mmol), iodine (74 mg, 0.129 mmol) and trans-N,N′-dimethylcycloesane-1,2-diammine were added. The mixture was then heated at 150° C. for 12 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 8/2/) to 35 mg of the title compound (50% yield).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[CH2:3][C:4](=[O:6])[CH3:5].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)CC(O)CCSc1ccccc1C(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccccc1C(F)(F)F
Yield: 99.4 %

Procedure:
13.53 Grams of 4-hydroxy-6-(2-trifluoromethylphenylthio)-2-hexanone were dissolved in 150 ml of toluene, and 0.71 g of oxalic acid was added thereto. The resulting mixture was refluxed for 3.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 12.93 g of 6-(2-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =4.4 : 1) (purity: 97.6%). The product was further column chromatographed to obtain a purified product having a refractive index (nD19) of 1.5263. The yield was 99.4%.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:41])[CH2:24][NH:25][C:26](=[O:40])/[CH:27]=[CH:28]/[C:29]2[CH:30]=[N:31][C:32]([C:35]([O:37]CC)=[O:36])=[CH:33][CH:34]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[OH-].[Na+].Cl>C(O)C>[C:35]([C:32]1[N:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:26]([NH:25][CH2:24][C:23]([N:21]([C:20]2[C:2]([Cl:1])=[C:3]([C:17]([Cl:42])=[CH:18][CH:19]=2)[CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]3)[CH3:22])=[O:41])=[O:40])=[CH:34][CH:33]=1)([OH:37])=[O:36]
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of 8-[2,6-dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (2.07 g) in ethanol (20 ml) was added 1N sodium hydroxide solution (3.75 ml) at ambient temperature. The mixture was stirred for 3 hours at 60° C. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid and concentrated. The residue was purified by flash chromatography (dichloromethane--methanol) to give 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (1.71 g) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N+:9](=[N:12]C(=O)C2C=CC=CC=2)[CH2:8][CH:7]=1)=[O:5])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/I)=[CH:24][CH:23]=1>[Pd](Br)Br.[O-]S(C(F)(F)F)(=O)=O.[Ag+].O1CCOCC1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[CH:10][N:9]3[N:12]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1=CC[N+](=NC(=O)c2ccccc2)C=C1
Reactant: Brc1ccc(/C=C/I)cc1
Agent: Br[Pd]Br
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Temperature: 127.5 °C
Yield: 54 %

Procedure:
Related procedures are described in Org. Lett. 2010, 12, 516): 4-Ethoxycarbonyl-N-benzoyliminopyridinium ylid (JOC 2003, 68, 7119) (3.50 g, 13.0 mmol), para-tris-methoxyphenylphosphine (686 mg, 1.95 mmol), Palladium (II) bromide (173 mg, 0.65 mmol), silver triflate (8.93 g, 39.0 mmol) and (E)-1-Bromo-4-(2-iodovinyl)benzene (Org. Lett. 2008, 10, 5485) (4.02 g, 13.0 mmol) were placed in a 250 mL round bottom flask equipped a with magnetic stirrer. Dioxane (52 mL) was added. The mixture was degassed by bubbling nitrogen for 10 minutes with vigorous stirring and heated to 125-130° C. for 15-20 h. The mixture was then cooled to room temperature, diluted with CH2Cl2, filtered over Celite. The organic layer was then washed with saturated aqueous sodium bicarbonate and the organic phase was concentrated under reduced pressure. The crude product was triturated with methanol to afford 2.40 g (54%) of the title compound. LCMS m/z 345.0, 347.0 (M+H)+, ret. time=3.05 min.