Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]=1[O:15]COC)[CH2:10][NH2:11].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([N:31](C2C=CC([N+]([O-])=O)=CC=2)[C:32](=O)[O-:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:8]=[C:9]([CH2:10][NH:11][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])[CH:12]=[C:13]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:14]=1[OH:15]
Reactant: CSc1ccc(N(C(=O)[O-])c2ccc([N+](=O)[O-])cc2)cc1
Reactant: COCOc1c(-c2sccc2C)cc(CN)cc1C(C)(C)C
Solvent: Cc1ccccc1
Product: CSc1ccc(NC(=O)NCc2cc(-c3sccc3C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.9 %

Procedure:
To a solution of 4.2 g (12.2 mmol) of the compound of Example 3 dissolved in 50 ml of toluene were added 3.70 g (12.2 mmol) of the compound of Example 12. The resulting solution was heated to reflux, stirred at that temperature for 45 minutes and then cooled to room temperature. Any solid particulates which had precipitated upon cooling were removed by filtration and the filtrate was concentrated to dryness to provide a residue. This residue was purified by column chromatography (10-40% ethyl acetate in hexane gradient as eluent) and fractions containing the desired product were combined and concentrated to dryness to provide 3.33 g of title compound.
Reaction SMILES: C(O)(C)C.C(O[K])(C)(C)C.[CH:11]1(/[CH:17]=[CH:18]/B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1>ICCC.O>[CH:11]1(/[CH:17]=[CH:18]/[C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(Br)cc1F
Reactant: OB(O)/C=C/C1CCCCC1
Agent: CC(C)(C)O[K]
Solvent: CC(C)O
Solvent: CCCI
Solvent: O
Product: Nc1ccc(/C=C/C2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
Isopropanol (60 mL) was added to PEPPSI™-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added trans-(2-cyclohexylvinyl)boronic acid (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g).
Reaction SMILES: FC1C=CC2CC(=O)C3C=C(C(C)C)C=CC=3SC=2C=1.CN1CCNCC1.C(O)(=O)/C=C\C(O)=O.C([O-])(=O)/C=C\C([O-])=O.[F:44][C:45]1[CH:46]=[CH:47][C:48]2[CH:54]=[C:53]([N:55]3[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]3)[C:52]3[CH:62]=[C:63]([CH:66]([CH3:68])[CH3:67])[CH:64]=[CH:65][C:51]=3[S:50][C:49]=2[CH:69]=1>C1C=CC=CC=1.C(O)C.[Ti](Cl)(Cl)(Cl)Cl.CCOCC.O>[F:44][C:45]1[CH:46]=[CH:47][C:48]2[CH2:54][CH:53]([N:55]3[CH2:56][CH2:57][N:58]([CH3:61])[CH2:59][CH2:60]3)[C:52]3[CH:62]=[C:63]([CH:66]([CH3:67])[CH3:68])[CH:64]=[CH:65][C:51]=3[S:50][C:49]=2[CH:69]=1
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(C)CC1)=Cc1ccc(F)cc1S2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)c1ccc2c(c1)C(=O)Cc1ccc(F)cc1S2
Agent: CN1CCNCC1
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(F)cc1S2

Procedure:
A stirred solution of 8.0 g 3-fluoro-8-isopropyldibenzo(b,f)thiepin-10(11H)-one in 55 ml benzene is treated with a solution of 2.8 g titanium tetrachloride in 14 ml benzene added dropwise. 14 g of 1-methylpiperazine are then slowly added and the mixture refluxed for 16 hours. After cooling, it is decomposed with 80 ml water, added dropwise. 100 ml benzene are then added and the separated solid is filtered. The benzene layer of the filtrate is washed with water, dried with potassium carbonate and evaporated. There are obtained 9.2 g (89%) crude oily base which is neutralized with maleic acid in ethanol. Addition of ether separates the crystalline maleate of 3-fluoro-8-isopropyl-10-(4-methylpiperazino)dibenzo(b,f)thiepin melting at 183°-184° C. with decomposition (ethanol-ether).
Reaction SMILES: [F:1][C:2]1([F:18])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13][C:12]3=[NH:17])=[CH:10][C:4]=2[O:3]1.[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(#N)C.C(Cl)Cl>[F:18][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C:14](=[CH2:16])[S:13]/[C:12]/3=[N:17]\[C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[CH:10][C:4]=2[O:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)C(=N)S1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CC#N
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2ccnc2)S1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylenethiazolidin-2-imine (Example 115, 0.2 g, 0.74 mmol) and carbonyldiimidazole (0.14 g, 0.92 mmol) in dry acetonitrile (5 mL) was stirred at 70° C. for 16 hours. After cooling down, the mixture was diluted with 150 mL of CH2Cl2 and washed successively with saturated sodium bicarbonate (75 mL), water (75 mL) and brine (75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed over silica using 100% CH2Cl2 to CH2Cl2:MeOH 95:5 as mobile phase to give the titled compound. 1H NMR (CD3OD) δ ppm 5.00 (2H), 5.40 (1H), 5.50 (1H), 6.90 (1H), 7.35 (2H), 7.44 (1H), 7.50 (1H), 8.05 (1H); MS (ESI) m/z 365(M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH:9]=[C:8]2[CH2:10][CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]3([CH3:22])[CH:7]2[CH2:6][CH2:5]1)[CH3:3].P(Cl)(Cl)[Cl:24].CN(C=O)C>C1COCC1>[CH3:18][C@:17]1([C:19]([Cl:24])=[O:20])[CH:12]2[C@@:13]([CH3:22])([CH:7]3[C:8]([CH:10]=[CH:11]2)=[CH:9][CH:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]3)[CH2:14][CH2:15][CH2:16]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C1C=C2C=CC3[C@](C)(CCC[C@@]3(C)C(=O)Cl)C2CC1
Yield: 93.3 %

Procedure:
A mixture of dihydroabietic acid (1.0 eq. 9.95 mmol), phosphorous (III) chloride (1.1 eq. 10.95 mmol) and DMF (0.1 ml) is refluxed overnight in THF (20 ml). The reaction mass is filtered under suction and concentrated under vacuum to give 2.98 g (93%) yellow oil. The compound is used immediately for the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccccc1Cl

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chlorobenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 343.1 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl[CH2:35][CH2:36][CH2:37][S:38]([N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)(=[O:40])=[O:39]>>[CH3:47][N:44]1[CH2:43][CH2:42][N:41]([S:38]([CH2:37][CH2:36][CH2:35][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][C:3]=2[O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)(=[O:40])=[O:39])[CH2:46][CH2:45]1
Reactant: CN1CCN(S(=O)(=O)CCCCl)CC1
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Product: CN1CCN(S(=O)(=O)CCCOc2c(OCCCN3CCOCC3)ccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)CC1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and 1-[(3-chloropropyl)sulfonyl]-4-methylpiperazine (Intermediate D). High vacuum drying gave the title compound (29 mg, 27%): HPLC MS RT=0.23 min, MH+=655.6; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22-2.27 (4H, m), 2.82 (3H, s), 3.09-3.18 (6H, m), 3.29-3.32 (2H, m), 3.45-3.52 (6H, m), 3.64-3.70 (2H, m), 3.77-3.80 (2H, m), 3.99-4.01 (2H, m), 4.24-4.29 (2H, m), 4.32-4.36 (4H, m), 4.55-4.60 (2H, m), 7.49 (1H, d), 7.90 (1H, dd), 8.09 (1H, d), 8.83 (1H, d), 8.98 (1H, dd), 9.47 (1H, d).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[CH:14][C:13]=2[N+:31]([O-:33])=[O:32])=[CH:7][CH:6]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S)=CC=1>CN(C=O)C.O>[N+:31]([C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH:16]=[CH:17][C:12]=1[S:11][C:8]1[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Agent: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 242b (600 mg, 1.828 mmol) was dissolved in DMF (20 mL) to which K2CO3 (505 mg, 3.656 mmol), and 4-methyl-benzenethiol (227 mg, 1.828 mmol) were added. This reaction mixture was then heated to 80° C. for 1 hr. At this time the reaction mixture was cooled to room temperature, diluted with water, and the title compound collected by filtration (611 mg, 77
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>O.CCO>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(F)cccc1I
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(F)cccc1I
Temperature: 0 °C
Yield: 59.2 %

Procedure:
To a mixture of 2-iodo-6-fluorobenzaldehyde (45 mmol) in H2O (22.5 ml), EtOH (22.5 ml), and ice (20 g) was added hydroxylamine hydrochloride (3.19 g, 49.5 mmol, 1.1 eq.). Then, 112.5 mmol of 50% NaOH (4.5 g in 4.5 ml H2O, 2.5 eq.) was added with stirring. Enough ice to keep the temperature at 25-30° C. was added. The reaction was stirred for 2 h, acidified with conc. HCl to pH 4 (ice was added to keep the temperature at 25-30° C.), and extracted with Et2O. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel using ethyl acetate in hexanes (5%-10%) to give 2-iodo-6-fluorobenzaldehyde oxime (7.06 g, 59% over 2 steps) as an oil that solidified over time.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]([C:33]([OH:35])=O)[CH2:5]1.[NH2:36][OH:37]>>[OH:37][NH:36][C:33]([CH:6]1[CH:7]([NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)=[O:35]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(CCO)CC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(CCO)CC3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.4 g (0.8 mmol) of 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid and hydroxylamine afforded a ˜2:1 mixture of cis- and trans-1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid hydroxyamide as an amorphous white solid (0.040 g, 9.7%) after purification using reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient. MS: 515 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(F)c(F)c2)cn1
Yield: 15 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluoro-phenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3,4-difluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (16 mg, 15%) which was obtained as an off-white solid. MS: m/e=356.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)N(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL) was added dimethylcarbamic chloride (39 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-N,N-dimethylpiperidine-1-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: COc1ccc(Br)c2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Temperature: 25 °C
Yield: 34 %

Procedure:
A stirring mixture of 4-bromo-7-methoxyindole LII (162 mg, 0.717 mmol), ethyl cinnamate (254 mg, 1.43 mmol), tetra-butylammonium bromide (46 mg, 0.143 mmol), TEA (199 μl, 1.43 mmol) and palladium-dichloro-[bis-(tri-ortho-tolyl)phosphine] (28 mg, 0.036 mmol) in DMF (2 ml) was heated in a sealed vial flushed with N2, at 110° C. for 20 hours. The reaction was cooled to room temperature and partitioned between H2O and EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The organics were combined dried over Na2SO4, filtered and evaporated. The crude mixture was purified via flash chromatography (hexane/EtOAc) affording 3-(7-methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (108 mg, 34% yield).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][NH2:5].[CH2:7]([O:14][C:15](SC1N=C(C)C=C(C)N=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([O:14][C:15]([NH:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:6])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccccc2)n1
Reactant: NCCCCN
Solvent: CO
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 22.5 %

Procedure:
Into 30 mL of 50% aqueous methanol, was dissolved 1.76 g (20 mmoles) of 1,4-butanediamine followed by the addition of 5.48 g (20 mmoles) of S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (a product of Kokusan Kagaku Co.). The mixture was stirred for 3 hours. Thereafter, the reaction mixture was filtered to remove the precipitated di-N-benzyloxycarbonyl compound [2.09 g (29%) were recovered], and the filtrate was evaporated to dryness. The residue was dissolved in 250 mL of chloroform, washed 5 times with 100 mL of water. The chloroform layer was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1.0 g (23% yield) of mono-N-benzyloxycarbonyl-1,4-butanediamine in colorless syrup form.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:10]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C#Cc1ccc(C=C)cc1
Reactant: Oc1ccccc1I
Product: C=Cc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and 2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (300 mg, 68% yield). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.45, 2H), 7.56-7.44 (m, 4H), 7.29-7.19 (m, 2H), 6.98 (s, 1H), 6.74 (dd, J=10.93 and J=6.59, 1H), 5.78 (d, J=17.71, 1H), 5.28 (d, J=10.93, 1H). 13C NMR (75 MHz, CDCl3) δ 155.66, 154.87, 137.69, 136.26, 129.75, 129.22, 126.61, 125.02, 124.28, 122.94, 120.87, 114.40, 111.13, 101.37. Anal. Calcd. for C16H12O: C, 87.25; H, 5.49. Found C, 87.54; H, 5.62. m.p.: 164-165° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:33]2[O:32][CH:31]=[C:30]([Br:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[Cl:35]>>[Br:34][C:30]1[C:29]2[CH:28]=[CH:27][C:26]([Cl:35])=[C:25]([NH:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:33]=2[O:32][CH:31]=1
Reactant: Nc1c(Cl)ccc2c(Br)coc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Nc3c(Cl)ccc4c(Br)coc34)ncnc2cc1OCCCN1CCOCC1
Yield: 66.4 %

Procedure:
Using an analogous procedure to that described in Example 3, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.13 g) was reacted with 7-amino-3-bromo-6-chlorobenzofuran (0.186 g) to give the title compound (0.14 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.15 (m, 2H), 3.35 (t, 2H), 3.55 (m, 2H), 3.7 (t, 2H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35 (t, 2H), 7.4 (s, 1H), 7.7 (d, 2H), 8.2 (s, 1H), 8.4 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 549.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=1)C=C)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[Si:25]([O:24][C@H:9]1[CH2:8][CH2:7][C@H:6]2[C@H:5]3[C@H:14]([CH2:13][CH2:12][C@:10]12[CH3:11])[C@:15]1([CH3:23])[C@H:20]([CH2:19][C:18](=[O:22])[CH2:17][CH2:16]1)[CH2:21][C@H:4]3[CH2:1][CH:2]=[CH:3][C:42]1[CH:45]=[C:46]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:47]=[C:40]([O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:41]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: C=CC[C@@H]1C[C@H]2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Reactant: C=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CC=Cc4cc(OCc5ccccc5)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 30 °C
Reaction time: 14 h

Procedure:
Under argon atmosphere, 7α-allyl-17β-(tert-butyldimethylsilyloxy)-5α-androstan-3-one (200 mg), 3,5-dibenzyloxystyrene (285 mg) and benzylidene-bis(tricyclohexylphosphine)-dichlororuthenium (37 mg) were dissolved in methylene chloride (2.5 ml) and stirred at 30° C. for 14 hours. After evaporation under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3,5-dibenzyloxyphenyl)-2-propenyl)-5α-androstan-3-one.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>C(OCC)C>[Cl:13][C:12]1[C:7]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Clc1cccnc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a −60° C. solution of n-butyl lithium (23 mL, 2.5M in hexane, 58.2 mmol) in diethyl ether (40 mL) was added a solution of 2-bromo-3-chloropyridine (Alfa, 8.0 g, 41.6 mmol) in diethyl ether (60 mL) over 15 minutes. The reaction mixture was stirred for 40 minutes followed by a slow addition (about 15 minutes) of a solution of 1,4-dioxaspiro[4.5]decan-8-one (Aldrich, 8.44 g, 54.0 mmol) in diethyl ether (100 mL), and stirred until reaction mixture warmed up to ambient temperature (about 3 hours). The mixture was quenched with saturated NH4Cl, diluted with ethyl acetate and washed with water. The organic layer was separated, concentrated and the residue crystallized from ethyl acetate-hexanes to obtain 5.5 g of the title compound. Two more crystallizations of the mother liquors yielded 1.61 g more material. Total yield 7.13 g (64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (d, J=12.69 Hz, 2H), 1.80 (d, J=12.69 Hz, 2H), 1.94 (td, J=12.69, 4.36 Hz, 2H), 2.30-2.41 (m, 2H), 3.88 (s, 4H), 5.36 (s, 1H), 7.36 (dd, J=7.93, 4.76 Hz, 1H), 7.88 (dd, J=7.93, 1.59 Hz, 1H), 8.48 (dd, J=4.76, 1.59 Hz, 1H). MS (DCI) m/z 270.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Yield: 0.1 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.84 g, 18.6 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 1.08 g, 27.0 mmol) under cooling with ice for 1 hour. The reaction mixture was stirred with triisopropylsilyl chloride (6.0 mL, 28 mmol) at room temperature for one day. After addition of water, the reaction mixture was warmed to room temperature and extracted with hexane twice. The resulting organic layers were combined, washed with saturated aqueous sodium chloride dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound as a reddish brown oil (5.74 mg, yield 99%).